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  • Effects of physical activity interventions on physical fitness in preschool children: a meta-analysis of randomized controlled trials and dose–response study | BMC Public Health

    Effects of physical activity interventions on physical fitness in preschool children: a meta-analysis of randomized controlled trials and dose–response study | BMC Public Health

    Characteristics of included studies

    Figure 1 presents the PRISMA flow diagram outlining the systematic search and selection process. The initial electronic screening identified 5030 potentially relevant articles. After title and abstract screening, 103 studies were deemed eligible and underwent full-text review. Subsequently, 14 RCTs met the inclusion criteria and were retained for meta-analysis.

    Fig. 1

    Flow chart of the study selection procedure

    The included RCTs were published between 2005 and 2023 (median year, 2014), comprising a total of 3376 participants (1683 boys), aged 3–7 years. Sample sizes ranged from 30 to 1434, with a mean participant age of 4.98 years (SD = 0.51). Intervention durations spanned 8–48 weeks (mean 20.62 weeks, SD 13.50), frequencies ranged from 1 to 5 sessions per week (mean 3.28, SD 1.17), and session lengths varied from 15 to 90 min (mean 36.40 min, SD 17.12).

    The number of independent data points differed by physical fitness outcome: upper muscle strength (10 studies) [26,27,28,29,30,31], lower muscle strength (14 studies) [6, 26,27,28,29,30,31,32,33,34], flexibility quality (10 studies) [26, 28,29,30,31, 34, 35], coordination (6 studies) [26,27,28,29,30, 33, 36][, cardiorespiratory fitness (CRF; 11 studies) [6, 26, 28,29,30,31,32], dynamic balance (11 studies) [26, 28, 29, 31, 36,37,38], and static balance (10 studies) [6, 27, 28, 30, 33, 37, 38]. Detailed study characteristics are presented in Supplementary 3.

    The results of pairwise meta-analysis

    Summary of overall physical fitness outcomes

    Seventy-three independent data points from 14 studies contributed to the analysis of overall physical fitness, which encompassed all measured sub-components. As depicted in Fig. 2, chronic PA interventions exerted a small but significant positive effect on overall physical fitness in preschool children (SMD = 0.30, 95% CI: 0.22 to 0.38, I2 = 72.8%, p < 0.001). Subgroup analyses demonstrated that intervention duration (≥ 16 weeks vs. < 16 weeks), session duration (≥ 40 min vs. < 40 min), and frequency (> 3 times/week vs. ≤ 3 times/week) each influenced the pooled effect size.

    Fig. 2
    figure 2

    Effects of physical activity on preschool children’s physical fitness with different moderators

    Muscle strength

    PA interventions significantly improved upper muscle strength (SMD = 0.30, 95% CI: 0.14 to 0.46, I2 = 33.2%, p < 0.001). In subgroup analyses, interventions ≥ 16 weeks in duration (SMD = 0.35, 95% CI: 0.15 to 0.54, I2 = 41.0%, p = 0.001), session lengths < 40 min (SMD = 0.41, 95% CI: 0.19 to 0.62, I2 = 35.1%, p < 0.001), and frequencies ≤ 3 times/week (SMD = 0.35, 95% CI: 0.16 to 0.53, I2 = 20.0%, p < 0.001) all yielded significant gains in upper muscle strength.

    PA interventions produced a significant improvement in lower muscle strength (SMD = 0.29, 95% CI: 0.12 to 0.46, I2 = 75.5%, p = 0.001). Subgroup analyses indicated meaningful effects in both < 16 weeks (SMD = 0.51, 95% CI: 0.23 to 0.80, I2 = 44%, p < 0.001) and ≥ 16 weeks of intervention (SMD = 0.20, 95% CI: 0.02 to 0.38, I2 = 74.4%, p = 0.031). Session length (≥ 40 min: SMD = 0.22, 95% CI: 0.01 to 0.43, I2 = 61.9%, p = 0.045; < 40 min: SMD = 0.36, 95% CI: 0.07 to 0.65, I2 = 80.8%, p = 0.014) also influenced lower muscle strength. Of note, only the > 3 times/week subgroup displayed significant improvement (SMD = 0.36, 95% CI: 0.11 to 0.61, I2 = 83.3%, p = 0.005).

    Flexibility quality

    PA interventions significantly enhanced flexibility (SMD = 0.27, 95% CI: 0.03 to 0.52, I2 = 72.4%, p = 0.028). Subgroup analyses revealed that session lengths ≥ 40 min (SMD = 0.33, 95% CI: 0.06 to 0.59, I2 = 54.9%, p = 0.016) and frequencies > 3 times/week (SMD = 0.65, 95% CI: 0.18 to 1.13, I2 = 79.6%, p = 0.007) contributed substantially to the observed improvement.

    CRF

    PA interventions led to a significant increase in CRF (SMD = 0.29, 95% CI: 0.10 to 0.48, I2 = 72.4%, p = 0.003). Subgroup analyses indicated significant improvements with both < 16 weeks (SMD = 0.32, 95% CI: 0.10 to 0.54, I2 = 0%, p = 0.005) and ≥ 16 weeks of intervention (SMD = 0.28, 95% CI: 0.04 to 0.52, I2 = 77.0%, p = 0.022), as well as with PA frequencies of > 3 times/week (SMD = 0.42, 95% CI: 0.04 to 0.80, I2 = 85.5%, p = 0.031) and ≤ 3 times/week (SMD = 0.20, 95% CI: 0.02 to 0.39, I2 = 27.0%, p = 0.031). Interestingly, the < 40-min session subgroup (SMD = 0.27, 95% CI: 0.05 to 0.49, I2 = 43.2%, p = 0.015) also showed notable CRF improvements.

    Coordination

    PA interventions significantly enhanced coordination (SMD = 0.54, 95% CI: 0.31 to 0.76, I2 = 57.5%, p < 0.001). All examined subgroups—longer (≥ 16 weeks: SMD = 0.49, 95% CI: 0.20 to 0.78, I2 = 65.7%, p = 0.001) versus shorter (< 16 weeks: SMD = 0.63, 95% CI: 0.34 to 0.91, I2 = 0.0%, p < 0.001) durations, longer (≥ 40 min: SMD = 0.50, 95% CI: 0.21 to 0.78, I2 = 68.4%, p = 0.001) versus shorter (< 40 min: SMD = 0.63, 95% CI: 0.31 to 0.96, I2 = 0.2%, p < 0.001) session lengths, and higher (> 3 times/week: SMD = 0.50, 95% CI: 0.26 to 0.75, I2 = 60.4%, p < 0.001) versus lower (≤ 3 times/week: SMD = 0.70, 95% CI: 0.13 to 1.26, I2 = 46.7%, p = 0.016) frequencies—exhibited statistically significant effects.

    Balance

    PA interventions significantly improved static balance (SMD = 0.38, 95% CI: 0.10 to 0.65, I2 = 80.7%, p = 0.007). Within subgroup analyses, frequencies of ≤ 3 times/week yielded a significant benefit (SMD = 0.33, 95% CI: 0.11 to 0.55, I2 = 43.8%, p = 0.003). All studies included in this analysis of static balance used ≥ 40-min PA sessions. No significant improvement was noted in dynamic balance, and subgroup analyses did not alter the null findings.

    The results of dose–response relationship

    Overall physical fitness

    A non-linear dose–response curve was identified between weekly PA dose (0–380 min/week) and overall physical fitness (Fig. 3). The optimal dose was approximately 270 min/week (SMD = 0.557, 95% CrI: 0.347 to 0.825), indicating that moderate-to-high volumes of structured PA may maximize improvements in preschool children’s global fitness levels.

    Fig. 3
    figure 3

    Dose–response relationship between overall exercise dose and change in the physical fitness

    Muscle strength

    An inverted U-shaped association emerged between weekly PA dose (0–350 min/week) and upper muscle strength (Fig. 4a). The optimal dose converged at approximately 260 min/week (SMD = 0.337, 95% CrI: 0.068 to 0.735), suggesting that interventions beyond this range may yield diminishing returns.

    Fig. 4
    figure 4

    Dose–response relationship between different exercise doses and change in the different specific fitness components

    Lower muscle strength displayed a similarly inverted U-shaped pattern (Fig. 4b), with effective doses spanning 0–350 min/week and an estimated optimum of around 260 min/week (SMD = 0.424, 95% CrI: 0.235 to 0.746). This finding aligns closely with that of upper muscle strength, emphasizing the importance of balancing intensity and volume.

    Flexibility quality

    Flexibility quality improved with PA volumes up to 340 min/week (Fig. 4c). The peak effect occurred at roughly 190 min/week (SMD = 0.345, 95% CrI: 0.078 to 0.739), suggesting that, compared with muscle strength outcomes, lower cumulative exercise doses may suffice to enhance flexibility quality in preschool populations.

    CRF

    Dose–response modeling for CRF (Figure 4d) demonstrated continued gains up to 380 min/week, with the maximum benefit at the highest dose examined (SMD = 0.255, 95% CrI: 0.106 to 0.496). This suggests that higher weekly PA volumes may be particularly advantageous for improving aerobic capacity in young children.

    Coordination

    Coordination displayed a wide range of effective doses, from 0 to 380 min/week (Fig. 4e). The apparent optimal volume reached approximately 300 min/week (SMD = 0.419, 95% CrI: 0.075 to 1.082). This finding highlights that motor skill development—particularly coordination—benefits from relatively high PA volumes.

    Static balance

    Improvements in static balance were most pronounced at doses up to 180 min/week (Fig. 4f), peaking around that threshold (SMD = 0.431, 95% CrI: 0.224 to 0.821). Compared with other outcomes (e.g., CRF and coordination), static balance may not require as high a weekly PA volume to achieve meaningful gains.

    Connectivity assessment

    A connectivity assessment was undertaken to verify adequate linkages among all dose levels. Insufficient connectivity may compromise statistical power and yield biased findings when direct comparisons are infeasible. The assessment confirmed no connectivity deficits among the examined PA doses, thereby supporting the robustness of the subsequent dose–response modeling (Supplementary 11).

    Quality assessment of evidence and risk of bias

    Overall, 10 studies (40%) exhibited a low risk of bias, 10 (40%) had an unclear risk, and 5 (20%) demonstrated a high risk of bias. Study-level details of risk of bias are provided in Supplementary 8. Except for upper muscle strength, several outcomes displayed relatively high heterogeneity (Supplementary 9). Publication bias was assessed via funnel plots and Egger’s tests. Potential publication bias was noted for flexibility, lower muscle strength, coordination, CRF, and static balance (p < 0.05), warranting cautious interpretation. The p-values for all remaining outcomes exceeded 0.05, indicating no significant publication bias in those measures (Supplementary 10).

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  • Research Progress of Mitochondrial Dynamics and Autophagy in Diabetic

    Research Progress of Mitochondrial Dynamics and Autophagy in Diabetic

    Introduction

    Diabetes is a metabolic disorder, and epidemiological studies indicate that the prevalence of diabetes is increasing annually. By 2045, global projections estimate 783.2 million individuals will live with diabetes.1 Individuals with diabetes frequently develop macrovascular and microvascular pathologies, which give rise to complications that compromise quality of life and elevate mortality risk. These complications encompass cardiovascular disease, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. The core pathological pathway of diabetes mellitus involves absolute insulin deficiency (secondary to autoimmune destruction of pancreatic β-cells) or relative insulin insufficiency (attributed to insulin resistance), which induces impaired glucose uptake, utilization, and storage, thereby leading to chronic hyperglycemia and metabolic disturbances. As the central hub of cellular energy metabolism, mitochondrial dysfunction is closely linked to metabolic diseases. By regulating key processes including glucose oxidation, energy production, and insulin sensitivity, mitochondria are deeply involved in the pathological progression of diabetes, serving as a critical target for elucidating the mechanisms underlying its metabolic derangements. Emerging evidence highlights the critical role of mitochondrial function in the pathogenesis and progression of diabetic complications. Specifically, mitochondrial dynamics and autophagy have become central research focuses in elucidating the mechanisms underlying diabetes-associated tissue injury. Currently, there are drug studies targeting mitochondrial dynamics and autophagy, such as mitochondrial fission inhibitors and autophagy inducers.

    Mitochondria are dynamic organelles that continuously undergo fusion and fission to adapt to cellular metabolic demands and environmental changes.2 Mitochondrial fusion is mediated by key regulatory proteins, such as mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1).3,4 During fusion, mitochondria exchange mitochondrial genomic material, proteins, and metabolites, facilitating cellular adaptive responses under stress and optimizing mitochondrial function. In contrast, mitochondrial fission is regulated by dynamin-related protein 1 (DRP1), fission protein 1 (FIS1), and mitochondrial fission factor (MFF).5 Fission promotes the biogenesis of new mitochondria and the elimination of damaged organelles, thereby safeguarding cellular homeostasis. The equilibrium between mitochondrial fusion and fission is essential for cellular survival and function, whereas disruptions in this balance can induce cell death and pathological conditions.6

    Mitophagy is a selective form of autophagy responsible for the removal of damaged or redundant mitochondria, thereby maintaining mitochondrial quality and quantity homeostasis within the cell.7 The molecular mechanisms of mitophagy are broadly categorized into two primary pathways: ubiquitin-dependent and ubiquitin-independent pathways. Among these, the PTEN-induced kinase 1 (PINK1)-Parkin (E3 ubiquitin ligase) pathway represents the best-characterized ubiquitin-dependent signaling cascade in mitophagy.8 Mitophagy is a highly intricate and finely regulated biological process, and in-depth investigation of its mechanisms may provide new avenues for disease diagnosis and therapeutic interventions.9

    Accumulating evidence indicates that MFN1, MFN2, and Parkin play key roles in both mitochondrial dynamics and mitophagy, establishing a functional link between these two processes.10–12 This review focuses on summarizing the roles of mitochondrial dynamics and mitophagy in diabetic complications, elucidating their specific mechanisms, and discussing potential strategies for restoring mitochondrial function to mitigate the impact of diabetic complications. These insights may provide valuable references for further understanding the pathogenesis of diabetic complications and identifying novel therapeutic targets.

    Mitochondrial Dynamics, Mitophagy and Diabetic Cardiomyopathy

    Diabetic cardiomyopathy (DCM) is a diabetes-related myocardial disorder characterized by cardiac structural and functional alterations independent of other established cardiovascular risk factors. Without intervention, DCM can progress to heart failure, arrhythmias, cardiogenic shock, and sudden cardiac death.13 In acute heart failure populations, the estimated prevalence of DCM is 1.6%.14 The pathogenesis of DCM is multifactorial, encompassing hyperglycemia, mitochondrial dysfunction, apoptosis, fibrosis, metabolic disorders, inflammatory responses, and the accumulation of advanced glycation end products (AGEs).15,16 Hyperglycemia induces oxidative stress, resulting in excessive reactive oxygen species (ROS) production, which impairs mitochondrial function in cardiomyocytes and exacerbates metabolic dysregulation. Elevated oxidative stress directly disrupts mitochondrial dynamics, altering the balance between fusion and fission, which impairs myocardial energy supply and contributes to cardiac dysfunction.17,18 Mitochondrial dynamics and autophagy constitute the core components of the mitochondrial quality control system, tasked with eliminating damaged mitochondria, regulating mitochondrial morphology, and maintaining cardiac energy homeostasis.19 Thus, maintaining mitochondrial homeostasis is essential for preserving cardiac metabolic integrity and halting the progression of DCM.

    Excessive nutrient consumption disrupts mitochondrial fusion, fission, and autophagy processes in cardiomyocytes, thereby compromising mitochondrial homeostasis and cardiac function.20 In DCM, diminished mitochondrial fusion capacity, coupled with either excessive or inadequate mitochondrial fission, leads to a deterioration of mitochondrial quality, causing an imbalance in the number and function of mitochondria within cardiomyocytes. Under hyperglycemic conditions, DRP1 orchestrates mitochondrial fission in rat cardiomyocytes, which promotes the overproduction of ROS. Tetracycline has been demonstrated to induce the upregulation of MFN2, thus maintaining mitochondrial function.21 Similarly, in obese mice with DCM, DRP1 expression is significantly increased, while the levels of MFN1 and MFN2 are substantially decreased.22 Studies have also demonstrated that prenatal exposure to a high-glucose and high-fat diet results in shorter and wider mitochondria in neonatal rat cardiomyocytes, which subsequently impairs mitochondrial function.23 Additionally, post-translational modifications are pivotal in regulating proteins associated with mitochondrial dynamics. Hyperglycemia enhances O-linked N-acetylglucosamine (O-GlcNAc) glycosylation of OPA1, exacerbating mitochondrial dysfunction.24 DRP1 undergoes O-GlcNAc modification at threonine residues 585 and 586, which elevates the level of its GTP-bound active form. This modification facilitates the translocation of DRP1 from the cytoplasm to the mitochondria, inducing mitochondrial fission and decreasing mitochondrial membrane potential, thus further exacerbating mitochondrial dysfunction in DCM.25

    Mitophagy exerts a pivotal function in cardiac development and maturation.26 Impaired mitophagy leads to mitochondrial dysfunction and lipid accumulation, exacerbating the progression of DCM. Accumulating evidence indicates that the loss of Parkin inhibits mitophagy,27 leading to enhanced lipid accumulation and deteriorated diastolic dysfunction. Conversely, the activation of mitophagy mitigates mitochondrial dysfunction, diminishes lipid accumulation, and improves diastolic function.28 FUN14 domain-containing protein 1 (FUNDC1) serves as a mitophagy receptor, interacting with microtubule-associated protein 1 light chain 3 (LC3) to initiate mitophagy in mammalian cells. The interaction among FUNDC1, DRP1, and OPA1 contributes to the regulation of mitochondrial fission, fusion, and mitophagy, thus maintaining mitochondrial quality control (Figure 1).29 Notably, emerging research has demonstrated that downregulating FUNDC1 expression alleviates mitochondrial calcium overload, ultimately improving DCM outcomes.30 Overall, a more profound understanding of mitochondrial dynamics and mitophagy mechanisms may lay the foundation for more efficacious therapeutic strategies and drug development for DCM in the future (Table 1).

    Table 1 Comparison of the Roles of Key Molecules Regulating Mitochondrial Function in Diabetes-Related Complications

    Figure 1 The role and mechanism of mitochondrial dynamics and autophagy in diabetic complications, as well as related potential therapeutic targets.

    Abbreviations: MFN1, mitofusin 1; MFN2, mitofusin 2; OPA1, optic atrophy 1; DRP1, dynamin-related protein 1; FIS1, fission protein 1; MFF, mitochondrial fission factor; PINK1, PTEN-induced kinase 1; DCM, diabetic cardiomyopathy; AGEs, advanced glycation end products; ROS, reactive oxygen species; O-GlcNAc, O-linked N-acetylglucosamine; FUNDC1, FUN14 domain-containing protein 1; LC3, light chain 3; DN, diabetic nephropathy; CKD, chronic kidney disease; PKM2, pyruvate kinase M2; PACS-2, phosphofurin acidic cluster sorting protein 2; MAM, mitochondrial-associated membrane; FOXO1, fork head box protein O1; PGRN, progranulin; mtDNA, mitochondrial DNA; DPN, diabetic peripheral neuropathy; TNF-α, tumor necrosis factor-α; IL-1, interleukin-1; IL-6, interleukin-6; Mul1, mitochondrial ubiquitin ligase 1; ER, endoplasmic reticulum; DR, diabetic retinopathy; NGR1, notoginsenoside R1; TXNIP, thioredoxin-interacting protein; Sirt3, sirtuin 3; LRP6, low density lipoprotein receptor – related protein 6; SGLT-2, sodium-glucose cotransporter-2; TCM, traditional Chinese medicine; TLN, tangluoning; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; KD, ketogenic diet; Arfip2, ADP-Ribosylation Factor-Interacting Protein 2; PARP1, poly (ADP-ribose) polymerase 1; SGLT-2, sodium-glucose cotransporter-2; HIF-1α, Hypoxia-inducible factor-1α; JCYSTL, Jin-Chan-Yi-Shen Tong-Luo formula; SBN, Silybin; PCN, Piceatannol.

    Mitochondrial Dynamics, Mitophagy and Diabetic Nephropathy

    Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and a leading cause of chronic kidney disease (CKD) and end-stage renal disease, affecting approximately 700 million people worldwide.44 The pathogenesis of DN is multifactorial, encompassing metabolic derangements, hemodynamic changes, immune-inflammatory responses, cellular and molecular mechanisms, and genetic susceptibility.45,46 Under hyperglycemic conditions, excessive generation of ROS and the accumulation of AGEs induce cellular dysfunction and renal cell injury.46 Moreover, diabetes is frequently associated with hypertension, which exacerbates glomerular hyperfiltration, leading to glomerular hypertrophy, tubulointerstitial fibrosis, ultimately impairing renal function.46

    Mitochondrial fission is intricately linked to the pathogenesis of DN. In diabetic mice, podocyte-specific deletion of DRP1 diminishes proteinuria, attenuates mesangial matrix expansion, and maintains podocyte morphology. Evidence from both in vivo and in vitro models indicates that DRP1 inhibition enhances mitochondrial adaptability in podocytes, mitigates excessive mitochondrial fission, and retards DN progression, thereby improving renal injury in diabetic mice.47 Pyruvate kinase M2 (PKM2) is a key regulator of podocyte development and promotes OPA1 expression to maintain mitochondrial stability (Figure 1).33,48 Additionally, the overexpression of phosphofurin acidic cluster sorting protein 2 (PACS-2) has been shown to inhibit DRP1 mitochondrial recruitment, reducing high glucose-induced mitochondrial hyperfission. This restoration of mitochondrial-associated membrane (MAM) integrity enhances mitophagy, as demonstrated in the renal tubules of diabetic mice and in PACS-2-overexpressing HK-2 cells. These changes are closely associated with alterations in mitochondrial dynamics and mitophagy-related proteins, including DRP1 and Beclin-1.35,49

    Preclinical evidence demonstrates that suppressing mitophagy in podocytes drives the progression of DN.50 The progression of DN is associated with a gradual decline in Parkin expression in renal tubular epithelial cells of diabetic patients, whereas Parkin overexpression has been found to alleviate inflammation and improve renal function in STZ-induced diabetic mice.51 In both Arfip2-knockout human podocytes and Arfip2-knockout combined with STZ-induced diabetic mouse models, Arfip2 deficiency exacerbates autophagic dysfunction in mice, leading to podocyte foot process effacement, histopathological changes, and early albuminuria, while in human podocytes, it disrupts ATG9A trafficking and the PINK1/Parkin pathway, resulting in impaired mitochondrial fission and reduced mitophagy; thus, Arfip2 may represent a novel regulator of podocyte autophagy and mitochondrial homeostasis.42 Fork head box protein O1 (FOXO1) transcriptionally activates PINK1, leading to the upregulation of Parkin expression and the initiation of mitophagy. Activation of FOXO1 has been shown to mitigate diabetes-induced podocyte injury in renal tubules and protect kidney function. Additionally, progranulin (PGRN), a secretory glycoprotein precursor, enhances mitophagy by promoting PINK1 and Parkin expression, thereby slowing the progression of DN. Moreover, DN patients display reduced mitochondrial DNA (mtDNA) content, leading to impaired energy metabolism and metabolic inflexibility, which further exacerbates mitochondrial dysfunction and renal pathology.52 MtDNA mutations compromise mitophagy efficiency, as mitochondria with mtDNA mutations can evade mitophagic clearance.53 The cooperative interaction among FOXO1, Arfip2, PGRN, PINK1, and Parkin is essential for preserving podocyte integrity and represents a promising molecular target for DN therapy (Table 1).39,54,55

    Elucidating the mechanisms of mitochondrial dynamics and mitophagy, along with identifying key molecular targets, could pave the way for innovative therapeutic strategies in the management of DN.

    Mitochondrial Dynamics, Mitophagy and Diabetic Peripheral Neuropathy

    Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes, typically manifesting as symmetrical pain and sensory abnormalities in the lower limbs. The pathogenesis of DPN is closely associated with hyperglycemia, dyslipidemia, and insulin resistance.56 Hyperglycemia-induced metabolic disorders lead to elevated ROS levels, resulting in oxidative stress that damages neuronal cell membranes and intracellular molecules, ultimately causing neuronal injury.57 Moreover, hyperglycemia triggers an inflammatory response, increasing the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). This inflammatory milieu exacerbates neuronal dysfunction and promotes apoptotic cell death, further deteriorating neural integrity in DPN.58

    Mitochondria play a crucial role in the pathophysiology of DPN. Mitochondrial dysfunction in DPN is characterized by excessive ROS production, calcium homeostasis imbalance, decreased mitochondrial membrane potential, ATP depletion, and subsequent impairments in axonal transport or increased apoptotic factors.59 These diabetes-induced structural and functional mitochondrial alterations directly compromise neuronal energy metabolism and metabolic equilibrium, thereby exacerbating neuronal dysfunction in DPN.60 Mitochondrial dynamics are essential for synaptic function, and the loss of MFN2 impairs axonal mitochondrial transport, disrupting energy supply to neurons and exacerbating metabolic deficits.31 Furthermore, mitochondrial dynamics are closely linked to the PKA/AKAP1 signaling pathway. PKA-mediated phosphorylation regulates mitochondrial morphology by modulating DRP1, a process crucial for maintaining neuronal structure and function. Excessive phosphorylation of DRP1 leads to excessive mitochondrial fission, leading to compromised energy metabolism and neuronal structural instability.36,61 Given these findings, targeting mitochondrial dynamics may represent a promising therapeutic strategy for DPN (Table 1).

    Moreover, mitochondrial dysfunction augments neuronal energy demands, thereby exacerbating synaptic impairment and neurological dysfunction. Within this pathological context, mitophagy functions as a selective quality-control mechanism, critically mitigating neuronal injury and promoting neuronal survival. Neurons require a continuous supply of energy to maintain synaptic transmission and long-distance axonal transport. Insufficient autophagosome load leads to the release of large amounts of ROS from damaged mitochondria, resulting in DNA fragmentation and protein misfolding. However, persistent hyperglycemia may cause the autophagosome load to exceed the normal threshold, leading to reduced autophagic efficiency and accumulation of autophagosomes.62,63 Mitochondrial ubiquitin ligase 1 (Mul1) suppresses Parkin-mediated mitophagy in mature neurons by maintaining the contact sites between the endoplasmic reticulum (ER) and mitochondria. Experimental evidence indicates that Mul1 deficiency upregulates MFN2 activity, inducing excessive mitochondrial fusion, and functions as an antagonist of ER-mitochondrial tethering, thereby decreasing ER-mitochondrial interactions. The diminished ER-mitochondria contact results in increased cytosolic calcium ion concentration, which activates calcineurin, subsequently triggering DRP1-dependent mitochondrial fission and mitophagy.64 Studies have shown that in db/db mouse models, poly(ADP-ribose) polymerase 1 (PARP1) induces peripheral nerve injury by inhibiting mitophagy in dorsal root ganglion neurons, whereas administration of PARP1 inhibitors ameliorates such nerve injury symptoms.40 Chronic dysregulation of calcium homeostasis may impair the balance between mitochondrial fission and fusion, resulting in decreased autophagic efficiency. Sustained hypercalcemia in neurons can inhibit mitochondrial mobility and impede the docking of autophagosomes with lysosomes.65 Furthermore, mitophagy facilitates the removal of excessive ROS and damaged mitochondria, thereby reducing oxidative stress, protecting neurons from damage, and extending their lifespan.66 Thus, modulating the interplay between MFN2, DRP1, and Parkin not only optimizes mitochondrial dynamics but also fine-tunes mitophagy, additionally, targeting such mechanisms as mitochondrial autophagic flux and calcium dynamics may represent a novel therapeutic strategy for DPN. (Figure 1).

    Mitochondrial Dynamics, Mitophagy and Diabetic Retinopathy

    Diabetic retinopathy (DR) is a common microvascular complication of diabetes, characterized by chronic and progressive retinal microvascular leakage and occlusion, leading to a series of fundus pathologies that result in visual impairment and even blindness. According to statistical data from 2020, approximately 1.07 million individuals worldwide have experienced blindness due to DR, while about 3.28 million have suffered from vision impairment caused by this condition.67 The pathogenesis of DR is multifactorial, encompassing hyperglycemia-driven metabolic derangements, inflammatory cascades, mitochondrial dysfunction, microvascular anomalies, pathological neovascularization, and neurodegenerative processes.68

    Hyperglycemia-induced inflammatory responses augment vascular permeability and retinal blood flow, ultimately culminating in apoptosis. Under hyperglycemic conditions, excessive generation of ROS inflicts damage on mitochondrial DNA, resulting in mitochondrial dysfunction and retinal impairment. Retinal ischemia and hypoxia exacerbate capillary endothelial cell injury, ultimately promoting neovascularization.69,70 In diabetic mice, the retinal expression of OPA1 is markedly decreased, resulting in mitochondrial swelling and localized constriction, thus facilitating mitochondrial fission. This phenomenon is associated with partial mitochondrial damage in the retinal capillaries of diabetic mice.34 In both in vivo and in vitro models of DR, overexpression of MFN2 in retinal endothelial cells has been demonstrated to safeguard against hyperglycemia-induced structural and functional mitochondrial damage, enhance mitochondrial DNA integrity and transcription, and mitigate the hyperglycemia-induced elevation in capillary cell apoptosis.32 In DR, the levels of MFN2 protein are decreased, whereas the levels of DRP1 are increased,37 resulting in augmented mitochondrial fission and compromised fusion. Excessive mitochondrial fragmentation initiates endothelial cell apoptosis, further exacerbating retinal vascular dysfunction.

    Under high-glucose conditions, Parkin accumulates within the mitochondria of retinal cells, thereby inducing mitophagy. However, in the diabetic retina of db/db mice, the mitophagosome-to-mitochondria ratio is reduced, accompanied by increased oxidative stress, which may be mediated by alterations in mitophagy-related proteins such as PRKN and PINK1.71 Notably, notoginsenoside R1 (NGR1) has been demonstrated to augment PINK1-Parkin–dependent mitophagy, thereby alleviating retinal cell damage.41 Müller cells, which are the predominant type of glial cells in the retina, play a crucial role in maintaining retinal function and homeostasis.72 Neurovascular coupling represents a core mechanism that sustains normal neural function—particularly visual function—by regulating vascular activity to match the metabolic demands of neurons in the retina and brain. When retinal neuronal activity increases, insufficient vascular dilation leads to inadequate blood flow and oxygen supply, triggering local hypoxia and damaging mitochondria in retinal neurons and glial cells such as Müller cells. This not only exacerbates energy metabolism disorders but also impairs the regulatory capacity of neurovascular coupling.73,74 Mitochondria are key regulators of neurovascular coupling. Under diabetic conditions, mitochondrial dysfunction induces abnormal signal transmission between neurons and vascular endothelial cells: excessive production of mitochondrial ROS inhibits the bioavailability of nitric oxide, impairs vasodilation, and aggravates retinal ischemia and hypoxia. Additionally, mitochondrial damage activates inflammatory pathways, promotes macrophage polarization, and further disrupts the blood-retinal barrier. The interplay between inflammation and mitochondrial dysfunction accelerates the progression of DR.75–77 Hyperglycemia induces an upregulation of thioredoxin-interacting protein (TXNIP) levels, promotes mitochondrial fission, and enhances autophagic flux in Müller cells. Silencing of TXNIP decreases both mitochondrial fission and autophagy in these cells,78 indicating that targeting TXNIP may represent a potential therapeutic strategy for diabetes and its associated complications, including DR (Figure 1).38,43 Moreover, the mitochondrial deacetylase Sirtuin 3 (Sirt3) is capable of activating mitophagy via the FOXO3a/PINK1-Parkin pathway, thereby safeguarding retinal pigment epithelial cells.79 The interaction between mitochondrial dynamics and autophagy exerts a significantly influence on retinal cell fate and overall health and function of the retina. The dynamic balance between these processes is essential for maintaining cellular homeostasis. Modulating the PINK1/Parkin pathway or inhibiting mitochondrial fission proteins, including DRP1, can effectively alleviate retinal cell damage and preserve visual function, presenting novel therapeutic approaches for DR. As research progresses, these insights could offer valuable guidance for the development of pharmacological interventions aimed at treating DR (Table 1).

    Application Prospects of Mitochondrial-Related Intervention Strategies in Diabetic Complications

    Mitochondria represent one of the most crucial organelles for maintaining cellular homeostasis. The interaction between mitochondrial dynamics and autophagy is fundamental for preserving organ function and regulating physiological processes. A more profound comprehension of these mechanisms may expedite the development of novel therapeutic strategies. Mitochondrial fission inhibitors, including Mdivi-1,80 P110, and DRP1i27,81 decrease DRP1 levels, inhibit mitochondrial fragmentation, and enhance mitochondrial fusion. Mdivi-1, a quinazolinone derivative, has been demonstrated to attenuate the activation of DRP1 signaling in vivo studies of end-stage DCM in mice (Figure 1). Specifically, Mdivi-1 alleviates autophagy inhibition and fatty acid metabolism dysregulation resulting from low density lipoprotein receptor – related protein 6 (LRP6) deficiency, ultimately ameliorating cardiac dysfunction.82 Melatonin improves mitochondrial function and cardiac function by inhibiting SIRT1/PGC-1α-dependent mitochondrial fission, which reduces the expression level of Drp1, thereby suppressing mitochondrial remodeling and oxidative stress, decreasing cardiomyocyte apoptosis.83 Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated the ability to prevent mitochondrial swelling, enhance mitochondrial repair and regeneration, and ameliorate mitochondrial dysfunction by inhibiting aberrant mitochondrial fission via the AMPK signaling pathway.84 Moreover, autophagy inducers including rapamycin have been proposed to alleviate diabetes-associated renal injury by promoting autophagic activation.48 As a deacetylase 1 activator, silybin (SBN) can ameliorate high glucose -induced sciatic nerve injury and oxidative damage in mouse neuroblastoma cells (N2A) and STZ-induced Sprague-Dawley rats, and exerts neuroprotective effects by enhancing mitophagy.85 Liraglutide prevents DR by inhibiting the PINK1/Parkin pathway, thereby reducing mitophagy.86

    Certain bioactive compounds derived from traditional Chinese medicine (TCM), including punicalagin and paeonol, have been demonstrated to attenuate oxidative stress by modulating mitochondrial fusion, thereby ameliorating DCM.87 Moreover, ginseng and its bioactive extracts exhibit protective effects against DCM by improving mitochondrial dysfunction.88 Berberine, a quaternary ammonium alkaloid extracted from Coptis chinensis (Huanglian) and Phellodendron amurense (Huangbai), enhances mitochondrial energy homeostasis by activating the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signaling pathway.89 Furthermore, berberine has been demonstrated to mitigate high-glucose-induced mitochondrial fission and fusion imbalance, as well as impairments in mitotic progression. It exerts protective effects against cardiomyocyte damage by promoting AMPK-dependent mitophagy activation, leading to reduced mitochondrial abundance and cellular injury.90 In high glucose/hypoxia-induced HK-2 cells and unilateral nephrectomy combined with STZ-induced diabetic kidney disease rat models, Jin-Chan-Yi-Shen Tong-Luo formula (JCYSTL) protects renal tubules against mitochondrial dysfunction and apoptosis by stabilizing HIF-1α to activate PINK1/Parkin-mediated mitophagy.91 Tangluoning (TLN), a TCM formulation, has been studied for its efficacy in preventing and treating DPN. In DPN rat models, TLN enhances mitochondrial function by inhibiting DRP1 expression and phosphorylation, thereby suppressing mitochondrial fission and upregulating fusion proteins MFN1, MFN2, and OPA1.92 Piceatannol (PCN), a SIRT1 activator, exerts neuroprotective effects by promoting mitobiogenesis and mitophagy through the SIRT1-PGC-1α-NRF2-TFAM and SIRT1-PINK1-Parkin axes.93 TCM offers significant promise in modulating mitochondrial function and autophagy, presenting novel therapeutic strategies for diabetic complications. TCM-based interventions targeting the PINK1/Parkin-mediated mitophagy pathway may exert neuroprotective effects in DN. Furthermore, the regulation of mitochondrial dynamics proteins, including MFN1, MFN2, and DRP1, may help restore mitochondrial homeostasis, presenting novel therapeutic insights for managing diabetes-related complications.94

    The ketogenic diet (KD) is a therapeutic dietary approach that influences mitochondrial dynamics by modulating the AMPK/mTOR signaling pathway.95 Regular physical exercise and a balanced dietary regimen can reduce excessive apoptosis, promote cellular health, and enhance mitochondrial function and autophagy (Table 2).96,97

    Table 2 Summary of Bioactive Compounds Targeting Mitochondrial Dynamics and Autophagy

    Diagnostic Monitoring and Precision Medicine Technologies for Diabetes Mellitus and Mitochondrial Dysfunction

    Accurate diagnosis of diabetes mellitus and monitoring of mitochondrial dysfunction are crucial for formulating effective management and intervention strategies. Mitochondrial dysfunction can be diagnosed and identified through metabolomics, proteomics analyses, and imaging techniques, while artificial intelligence has also shown great potential in processing diabetes-related multi-omics data, including genomics, proteomics, and metabolomics.

    Metabolomics analysis can characterize metabolic pathways and identify disease-related biomarkers by comprehensively detecting small-molecule metabolites in biological samples such as blood, urine, and tissues. This analysis can reveal systemic metabolic abnormalities and mitochondrial dysfunction, facilitating early disease detection and intervention. Among them, targeted metabolomics and flux analysis techniques can deeply dissect the mechanisms underlying mitochondrial metabolism and energy homeostasis, providing support for the development of personalized therapeutic approaches based on individual metabolic characteristics.98,99

    Imaging techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI), and near-infrared spectroscopy (NIRS) provide non-invasive diagnostic approaches for evaluating mitochondrial dysfunction in diabetes mellitus by visualizing in vivo mitochondrial function and tissue metabolism. Specifically, PET imaging uses radiolabeled tracers like [18F] fluorodeoxyglucose (FDG) and [11C] acetate to assess glucose uptake and oxidative metabolism in tissues, thereby facilitating in-depth understanding of mitochondrial function and energy metabolic status in diabetic tissues. MRI techniques, including magnetic resonance spectroscopy and diffusion-weighted imaging, can quantify tissue metabolites and water diffusion properties, providing information related to mitochondrial function and tissue microstructure.100,101

    Data-driven precision medicine provides innovative approaches for the prediction and management of type 2 diabetes mellitus (T2DM). With the advancement of big data and artificial intelligence technologies, the medical field can more accurately identify and predict T2DM risks. By integrating multi-dimensional data including genomics, metabolomics, lifestyle, and environment, artificial intelligence can not only analyze an individual’s genetic susceptibility and potential metabolic disorders but also comprehensively and dynamically monitor patients’ health status, thereby enabling early warning and personalized treatment of the disease.102

    Conclusion

    Mitochondrial dynamics and autophagy play critical roles in the pathogenesis and progression of diabetic complications. Mitochondrial dynamic imbalance, characterized by aberrant mitochondrial fusion and fission, results in diminished bioenergetic capacity, excessive ROS generation, and compromised mitophagy. These pathological changes are closely associated with the development of chronic diabetic complications, and their regulatory processes are complex and sophisticated, involving interactions among multiple signaling pathways and key molecules. However, due to the unclear regulatory mechanisms of these molecules, it is difficult to precisely target specific targets in mitochondrial dynamics and autophagy in practice, and single interventions fail to achieve satisfactory therapeutic efficacy, thus requiring the combined application of multiple approaches. With the rapid advancement of science and technology, combining omics technologies, artificial intelligence-based prediction, and novel imaging methods in the future is expected to improve diabetic complications through mitochondrial-targeted therapy. This review synthesizes the roles and molecular mechanisms of mitochondrial dynamics and autophagy in diabetic complications (Figure 1). Despite significant progress in recent studies, several unresolved issues remain, including unclear cross-talk between regulatory pathways, undefined epigenetic regulatory mechanisms, lack of systematic investigation into cell-type-specific differences, and insufficient research on the impacts of environmental and genetic factors. Future investigations should further clarify the precise regulatory mechanisms of mitochondrial dynamics and autophagy, while exploring their therapeutic potential for diabetic complications.

    Acknowledgments

    This work was supported by the “National Clinical Key Specialty Cultivation Project Platform for Endocrinology” (2024NMKFKT-01), and the “Yunnan Province Prosper Yunnan Talent Support Program” (YNWR-QNBJ-2018-070), and the “Reserve talents of young and middle-aged academic and technical leaders in Yunnan Province” (2018HB050).

    Disclosure

    The author(s) report no conflicts of interest in this work.

    References

    1. Sun H, Saeedi P, Karuranga S, et al. IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabet Res Clin Pract. 2022;183:109119. doi:10.1016/j.diabres.2021.109119

    2. El-Hattab AW, Scaglia F. Mitochondrial cytopathies. Cell Calcium. 2016;60(3):199–206. doi:10.1016/j.ceca.2016.03.003

    3. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160(2):189–200. doi:10.1083/jcb.200211046

    4. Belenguer P, Pellegrini L. The dynamin GTPase OPA1: more than mitochondria? BBA. 2013;1833(1):176–183. doi:10.1016/j.bbamcr.2012.08.004

    5. Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochemist. 2018;62(3):341–360. doi:10.1042/EBC20170104

    6. Al Ojaimi M, Salah A, El-Hattab AW. Mitochondrial fission and fusion: molecular mechanisms, biological functions, and related disorders. Membranes. 2022;12(9):893. doi:10.3390/membranes12090893

    7. Lu Y, Li Z, Zhang S, Zhang T, Liu Y, Zhang L. Cellular mitophagy: mechanism, roles in diseases and small molecule pharmacological regulation. Theranostics. 2023;13(2):736–766. doi:10.7150/thno.79876

    8. Li S, Zhang J, Liu C, et al. The role of mitophagy in regulating cell death. Oxid Med Cell Longev. 2021;2021:6617256. doi:10.1155/2021/6617256

    9. Wang H, Luo W, Chen H, Cai Z, Xu G. Mitochondrial dynamics and mitochondrial autophagy: molecular structure, orchestrating mechanism and related disorders. Mitochondrion. 2024;75:101847. doi:10.1016/j.mito.2024.101847

    10. Tanaka A, Cleland MM, Xu S, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by parkin. J Cell Biol. 2010;191(7):1367–1380. doi:10.1083/jcb.201007013

    11. Shirihai OS, Song M, Dorn GW. How mitochondrial dynamism orchestrates mitophagy. Circ Res. 2015;116(11):1835–1849. doi:10.1161/CIRCRESAHA.116.306374

    12. Kurihara Y, Kanki T, Aoki Y, et al. Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast. J Biol Chem. 2012;287(5):3265–3272. doi:10.1074/jbc.M111.280156

    13. Yokota S, Tanaka H, Mochizuki Y, et al. Association of glycemic variability with left ventricular diastolic function in type 2 diabetes mellitus. Cardiovasc Diabet. 2019;18(1):166. doi:10.1186/s12933-019-0971-5

    14. Matsushita K, Harada K, Kohno T, et al. Prevalence and clinical characteristics of diabetic cardiomyopathy in patients with acute heart failure. Nutr Metab Cardiovasc Dis. 2024;34(5):1325–1333. doi:10.1016/j.numecd.2023.12.013

    15. Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol. 2020;17(9):585–607. doi:10.1038/s41569-020-0339-2

    16. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Failure Rev. 2013;18(2):149–166. doi:10.1007/s10741-012-9313-3

    17. Gollmer J, Zirlik A, Bugger H. Mitochondrial mechanisms in diabetic cardiomyopathy. Diabet Metabol J. 2020;44(1):33–53. doi:10.4093/dmj.2019.0185

    18. Pappachan JM, Varughese GI, Sriraman R, Arunagirinathan G. Diabetic cardiomyopathy: pathophysiology, diagnostic evaluation and management. World Journal of Diabetes. 2013;4(5):177–189. doi:10.4239/wjd.v4.i5.177

    19. Poznyak AV, Ivanova EA, Sobenin IA, Yet SF, Orekhov AN. The role of mitochondria in cardiovascular diseases. Biology. 2020;9(6):137. doi:10.3390/biology9060137

    20. Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013;17(4):491–506. doi:10.1016/j.cmet.2013.03.002

    21. Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA. 2006;103(8):2653–2658. doi:10.1073/pnas.0511154103

    22. Hu L, Ding M, Tang D, et al. Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics. 2019;9(13):3687–3706. doi:10.7150/thno.33684

    23. Larsen TD, Sabey KH, Knutson AJ, et al. Diabetic pregnancy and maternal high-fat diet impair mitochondrial dynamism in the developing fetal rat heart by sex-specific mechanisms. Int J Mol Sci. 2019;20(12):3090. doi:10.3390/ijms20123090

    24. Makino A, Suarez J, Gawlowski T, et al. Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regulatory Integr Comp Physiol. 2011;300(6):R1296–302. doi:10.1152/ajpregu.00437.2010

    25. Gawlowski T, Suarez J, Scott B, et al. Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem. 2012;287(35):30024–30034. doi:10.1074/jbc.M112.390682

    26. Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309–314. doi:10.1038/nature14893

    27. Qiao H, Ren H, Du H, Zhang M, Xiong X, Lv R. [Retracted] Liraglutide repairs the infarcted heart: the role of the SIRT1/parkin/mitophagy pathway. Mol Med Rep. 2024;29(5):68. doi:10.3892/mmr.2024.13192

    28. Tong M, Saito T, Zhai P, et al. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res. 2019;124(9):1360–1371. doi:10.1161/CIRCRESAHA.118.314607

    29. Chen M, Chen Z, Wang Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy. 2016;12(4):689–702. doi:10.1080/15548627.2016.1151580

    30. Wu S, Lu Q, Ding Y, et al. Hyperglycemia-driven inhibition of amp-activated protein kinase α2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo. Circulation. 2019;139(16):1913–1936. doi:10.1161/CIRCULATIONAHA.118.033552

    31. Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the miro/milton complex. J Neurosci. 2010;30(12):4232–4240. doi:10.1523/JNEUROSCI.6248-09.2010

    32. Duraisamy AJ, Mohammad G, Kowluru RA. Mitochondrial fusion and maintenance of mitochondrial homeostasis in diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1617–1626. doi:10.1016/j.bbadis.2019.03.013

    33. Gong M, Guo Y, Dong H, et al. Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis. Phytomedicine. 2024;123:155247. doi:10.1016/j.phymed.2023.155247

    34. Kim D, Votruba M, Roy S. Opa1 deficiency promotes development of retinal vascular lesions in diabetic retinopathy. Int J Mol Sci. 2021;22(11):5928. doi:10.3390/ijms22115928

    35. Li C, Li L, Yang M, et al. PACS-2 ameliorates tubular injury by facilitating endoplasmic reticulum-mitochondria contact and mitophagy in diabetic nephropathy. Diabetes. 2022;71(5):1034–1050. doi:10.2337/db21-0983

    36. Dickey AS, Strack S. PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics. J Neurosci. 2011;31(44):15716–15726. doi:10.1523/JNEUROSCI.3159-11.2011

    37. Kim D, Sankaramoorthy A, Roy S. Downregulation of Drp1 and Fis1 inhibits mitochondrial fission and prevents high glucose-induced apoptosis in retinal endothelial cells. Cells. 2020;9(7):1662. doi:10.3390/cells9071662

    38. Devi TS, Yumnamcha T, Yao F, Somayajulu M, Kowluru RA, Singh LP. TXNIP mediates high glucose-induced mitophagic flux and lysosome enlargement in human retinal pigment epithelial cells. Biology Open. 2019;8(4):bio038521. doi:10.1242/bio.038521

    39. Li W, Du M, Wang Q, et al. FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/parkin pathway. Endocrinology. 2017;158(7):2155–2167. doi:10.1210/en.2016-1970

    40. Yuan P, Song F, Zhu P, et al. Poly (ADP-ribose) polymerase 1-mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model. J Neurochemist. 2022;162(3):276–289. doi:10.1111/jnc.15606

    41. Tien T, Zhang J, Muto T, Kim D, Sarthy VP, Roy S. High glucose induces mitochondrial dysfunction in retinal müller cells: implications for diabetic retinopathy. Invest Ophthalmol Visual Sci. 2017;58(7):2915–2921. doi:10.1167/iovs.16-21355

    42. Guo H, Rogg M, Keller J, et al. ADP-ribosylation factor-interacting protein 2 acts as a novel regulator of mitophagy and autophagy in podocytes in diabetic nephropathy. Antioxidants. 2024;13(1):81. doi:10.3390/antiox13010081

    43. Singh LP, Devi TS, Yumnamcha T. The role of txnip in mitophagy dysregulation and inflammasome activation in diabetic retinopathy: a new perspective. JOJ Ophthalmol. 2017;4(4):555643. doi:10.19080/JOJO.2017.04.555643

    44. Ellen KH. The epidemiology of diabetic kidney disease. Article. Kidney Dial. 2022;2(3):433–442. doi:10.3390/kidneydial2030038

    45. Raptis AE, Viberti G. Pathogenesis of diabetic nephropathy. Exp Clin Endocrinol Diabet. 2001;109 Suppl 2:S424–37.

    46. Samsu N. Diabetic nephropathy: challenges in pathogenesis, diagnosis, and treatment. Biomed Res Int. 2021;2021:1497449. doi:10.1155/2021/1497449

    47. Ayanga BA, Badal SS, Wang Y, et al. Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy. J Am Soc Nephrol. 2016;27(9):2733–2747. doi:10.1681/ASN.2015101096

    48. Fan X, Yang M, Lang Y, et al. Mitochondrial metabolic reprogramming in diabetic kidney disease. Cell Death Dis. 2024;15(6):442. doi:10.1038/s41419-024-06833-0

    49. Moulis M, Grousset E, Faccini J, Richetin K, Thomas G, Vindis C. The multifunctional sorting protein PACS-2 controls mitophagosome formation in human vascular smooth muscle cells through mitochondria-ER contact sites. Cells. 2019;8(6):638. doi:10.3390/cells8060638

    50. Guo F, Wang W, Song Y, et al. LncRNA SNHG17 knockdown promotes parkin-dependent mitophagy and reduces apoptosis of podocytes through Mst1. Cell Cycle. 2020;19(16):1997–2006. doi:10.1080/15384101.2020.1783481

    51. Chen K, Chen J, Wang L, et al. Parkin ubiquitinates GATA4 and attenuates the GATA4/GAS1 signaling and detrimental effects on diabetic nephropathy. FASEB J. 2020;34(7):8858–8875. doi:10.1096/fj.202000053R

    52. Czajka A, Ajaz S, Gnudi L, et al. Altered mitochondrial function, mitochondrial dna and reduced metabolic flexibility in patients with diabetic nephropathy. EBioMedicine. 2015;2(6):499–512. doi:10.1016/j.ebiom.2015.04.002

    53. Gilkerson RW, De Vries RL, Lebot P, et al. Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition. Human Mol Genet. 2012;21(5):978–990. doi:10.1093/hmg/ddr529

    54. Zhou D, Zhou M, Wang Z, et al. PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell Death Dis. 2019;10(7):524. doi:10.1038/s41419-019-1754-3

    55. Zhang X, Feng J, Li X, et al. Mitophagy in diabetic kidney disease. Front Cell Develop Biol. 2021;9:778011. doi:10.3389/fcell.2021.778011

    56. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabet Care. 2017;40(1):136–154. doi:10.2337/dc16-2042

    57. Hamid HS, Mervak CM, Münch AE, et al. Hyperglycemia- and neuropathy-induced changes in mitochondria within sensory nerves. Ann Clin Transl Neurol. 2014;1(10):799–812. doi:10.1002/acn3.119

    58. Chong ZZ, Menkes DL, Souayah N. Targeting neuroinflammation in distal symmetrical polyneuropathy in diabetes. Drug Discovery Today. 2024;29(8):104087. doi:10.1016/j.drudis.2024.104087

    59. Hernández-Beltrán N, Moreno CB, Gutiérrez-álvarez AM. Contribution of mitochondria to pain in diabetic neuropathy. Endocrinologia y nutricion. 2013;60(1):25–32. doi:10.1016/j.endonu.2012.03.005

    60. López-Doménech G, Kittler JT. Mitochondrial regulation of local supply of energy in neurons. Curr Opin Neurobiol. 2023;81:102747. doi:10.1016/j.conb.2023.102747

    61. Vital A, Vital C. Mitochondria and peripheral neuropathies. J Neuropathol Exp Neurol. 2012;71(12):1036–1046. doi:10.1097/NEN.0b013e3182764d47

    62. Parmar UM, Jalgaonkar MP, Kulkarni YA, Oza MJ. Autophagy-nutrient sensing pathways in diabetic complications. Pharmacol Res. 2022;184:106408. doi:10.1016/j.phrs.2022.106408

    63. Miceli C, Leri M, Stefani M, Bucciantini M. Autophagy-related proteins: potential diagnostic and prognostic biomarkers of aging-related diseases. Ageing Res Rev. 2023;89:101967. doi:10.1016/j.arr.2023.101967

    64. Puri R, Cheng XT, Lin MY, Huang N, Sheng ZH. Mul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts. Nat Commun. 2019;10(1):3645. doi:10.1038/s41467-019-11636-5

    65. Borbolis F, Ploumi C, Palikaras K. Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases. Npj Metabolic Health Dis. 2025;3(1):4. doi:10.1038/s44324-025-00049-2

    66. Lou G, Palikaras K, Lautrup S, Scheibye-Knudsen M, Tavernarakis N, Fang EF. Mitophagy and neuroprotection. Trends Mol Med. 2020;26(1):8–20. doi:10.1016/j.molmed.2019.07.002

    67. Curran K, Peto T, Jonas JB. Global estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 2000 to 2020. Eye. 2024;38(11):2047–2057. doi:10.1038/s41433-024-03101-5

    68. Wei L, Sun X, Fan C, Li R, Zhou S, Yu H. The pathophysiological mechanisms underlying diabetic retinopathy. Front Cell Develop Biol. 2022;10:963615. doi:10.3389/fcell.2022.963615

    69. Lechner J, O’Leary OE, Stitt AW. The pathology associated with diabetic retinopathy. Vision Res. 2017;139:7–14. doi:10.1016/j.visres.2017.04.003

    70. Madsen-Bouterse SA, Zhong Q, Mohammad G, Ho YS, Kowluru RA. Oxidative damage of mitochondrial DNA in diabetes and its protection by manganese superoxide dismutase. Free Rad Res. 2010;44(3):313–321. doi:10.3109/10715760903494168

    71. Zhou P, Xie W, Meng X, et al. Notoginsenoside R1 ameliorates diabetic retinopathy through PINK1-dependent activation of mitophagy. Cells. 2019;8(3):213. doi:10.3390/cells8030213

    72. Coughlin BA, Feenstra DJ, Mohr S. Müller cells and diabetic retinopathy. Vision Re. 2017;139:93–100. doi:10.1016/j.visres.2017.03.013

    73. Fletcher EL, Dixon MA, Mills SA, Jobling AI. Anomalies in neurovascular coupling during early diabetes: a review. Clin Exp Ophthalmol. 2023;51(1):81–91. doi:10.1111/ceo.14190

    74. Li Y, Liu Y, Liu S, et al. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther. 2023;8(1):152. doi:10.1038/s41392-023-01400-z

    75. Liu W, Tong B, Xiong J, et al. Identification of macrophage polarisation and mitochondria-related biomarkers in diabetic retinopathy. J Transl Med. 2025;23(1):23. doi:10.1186/s12967-024-06038-1

    76. Kowluru RA. Mitochondrial stability in diabetic retinopathy: lessons learned from epigenetics. Diabetes. 2019;68(2):241–247. doi:10.2337/dbi18-0016

    77. Kowluru RA, Mohammad G. Epigenetics and mitochondrial stability in the metabolic memory phenomenon associated with continued progression of diabetic retinopathy. Sci Rep. 2020;10(1):6655. doi:10.1038/s41598-020-63527-1

    78. Ao H, Li H, Zhao X, Liu B, Lu L. TXNIP positively regulates the autophagy and apoptosis in the rat müller cell of diabetic retinopathy. Life Sci. 2021;267:118988. doi:10.1016/j.lfs.2020.118988

    79. Huang L, Yao T, Chen J, et al. Effect of Sirt3 on retinal pigment epithelial cells in high glucose through Foxo3a/ PINK1-Parkin pathway mediated mitophagy. Exp Eye Res. 2022;218:109015. doi:10.1016/j.exer.2022.109015

    80. Maneechote C, Palee S, Kerdphoo S, Jaiwongkam T, Chattipakorn SC, Chattipakorn N. Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury. Clin Sci. 2018;132(15):1669–1683. doi:10.1042/CS20180510

    81. Rosdah AA, Abbott BM, Langendorf CG, et al. A novel small molecule inhibitor of human Drp1. Sci Rep. 2022;12(1):21531. doi:10.1038/s41598-022-25464-z

    82. Chen Z, Li Y, Wang Y, et al. Cardiomyocyte-restricted low density lipoprotein receptor-related protein 6 (LRP6) deletion leads to lethal dilated cardiomyopathy partly through Drp1 signaling. Theranostics. 2018;8(3):627–643. doi:10.7150/thno.22177

    83. Hu X, Lv J, Zhao Y, Li X, Qi W, Wang X. Important regulatory role of mitophagy in diabetic microvascular complications. J Transl Med. 2025;23(1):269. doi:10.1186/s12967-025-06307-7

    84. Liu X, Xu C, Xu L, et al. Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial fission via AMPK/SP1/PGAM5 pathway. Metabolism. 2020;111:154334. doi:10.1016/j.metabol.2020.154334

    85. Khan I, Preeti K, Kumar R, Khatri DK, Singh SB. Activation of SIRT1 by silibinin improved mitochondrial health and alleviated the oxidative damage in experimental diabetic neuropathy and high glucose-mediated neurotoxicity. Arch Physiol Biochem. 2024;130(4):420–436. doi:10.1080/13813455.2022.2108454

    86. Zhou HR, Ma XF, Lin WJ, et al. Neuroprotective role of GLP-1 analog for retinal ganglion cells via PINK1/parkin-mediated mitophagy in diabetic retinopathy. Front Pharmacol. 2020;11:589114. doi:10.3389/fphar.2020.589114

    87. Liu C, Han Y, Gu X, et al. Paeonol promotes Opa1-mediated mitochondrial fusion via activating the CK2α-Stat3 pathway in diabetic cardiomyopathy. Redox Biol. 2021;46:102098. doi:10.1016/j.redox.2021.102098

    88. Cao X, Yao F, Zhang B, Sun X. Mitochondrial dysfunction in heart diseases: potential therapeutic effects of Panax ginseng. Front Pharmacol. 2023;14:1218803. doi:10.3389/fphar.2023.1218803

    89. Qin X, Jiang M, Zhao Y, et al. Berberine protects against diabetic kidney disease via promoting PGC-1α-regulated mitochondrial energy homeostasis. Br J Pharmacol. 2020;177(16):3646–3661. doi:10.1111/bph.14935

    90. Hang W, He B, Chen J, et al. Berberine ameliorates high glucose-induced cardiomyocyte injury via AMPK signaling activation to stimulate mitochondrial biogenesis and restore autophagic flux. Front Pharmacol. 2018;9:1121. doi:10.3389/fphar.2018.01121

    91. Qiyan Z, Zhang X, Guo J, et al. JinChan YiShen TongLuo formula ameliorate mitochondrial dysfunction and apoptosis in diabetic nephropathy through the HIF-1α-PINK1-Parkin pathway. J Ethnopharmacol. 2024;328:117863. doi:10.1016/j.jep.2024.117863

    92. Zhu J, Yang X, Li X, Han S, Zhu Y, Xu L. Tang Luo Ning, a traditional chinese compound prescription, ameliorates schwannopathy of diabetic peripheral neuropathy rats by regulating mitochondrial dynamics in vivo and in vitro. Front Pharmacol. 2021;12:650448. doi:10.3389/fphar.2021.650448

    93. Khan I, Preeti K, Kumar R, Kumar Khatri D, Bala Singh S. Piceatannol promotes neuroprotection by inducing mitophagy and mitobiogenesis in the experimental diabetic peripheral neuropathy and hyperglycemia-induced neurotoxicity. Int Immunopharmacol. 2023;116:109793. doi:10.1016/j.intimp.2023.109793

    94. Zhao DM, Zhong R, Wang XT, Yan ZH. Mitochondrial dysfunction in diabetic nephropathy: insights and therapeutic avenues from traditional Chinese medicine. Front Endocrinol. 2024;15:1429420. doi:10.3389/fendo.2024.1429420

    95. Guo Y, Zhang C, Shang FF, et al. Ketogenic diet ameliorates cardiac dysfunction via balancing mitochondrial dynamics and inhibiting apoptosis in type 2 diabetic mice. Aging and Disease. 2020;11(2):229–240. doi:10.14336/AD.2019.0510

    96. Zhang F, Lin JJ, Tian HN, Wang J. Effect of exercise on improving myocardial mitochondrial function in decreasing diabetic cardiomyopathy. Exp Physiol. 2024;109(2):190–201. doi:10.1113/EP091309

    97. Kuo HY, Huang YH, Wu SW, et al. The effects of exercise habit on albuminuria and metabolic indices in patients with type 2 diabetes mellitus: a cross-sectional study. Medicina. 2022;58(5):577. doi:10.3390/medicina58050577

    98. Qiu S, Cai Y, Yao H, et al. Small molecule metabolites: discovery of biomarkers and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):132. doi:10.1038/s41392-023-01399-3

    99. Tanase DM, Gosav EM, Botoc T, et al. Depiction of branched-chain amino acids (BCAAs) in diabetes with a focus on diabetic microvascular complications. J Clin Med. 2023;12(18):6053. doi:10.3390/jcm12186053

    100. Hussain S, Mubeen I, Ullah N, et al. Modern diagnostic imaging technique applications and risk factors in the medical field: a review. Biomed Res Int 2022;2022:5164970. doi:10.1155/2022/5164970

    101. Tersalvi G, Beltrani V, Grübler MR, et al. Positron emission tomography in heart failure: from pathophysiology to clinical application. J Cardiovasc Dev Dis. 2023;10(5). doi:10.3390/jcdd10050220

    102. Tian X, Wang L, Zhang L, et al. New discoveries in therapeutic targets and drug development pathways for type 2 diabetes mellitus under the guidance of precision medicine. Eur J Med Res. 2025;30(1):450. doi:10.1186/s40001-025-02682-5

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  • How US could turn Pakistan into an energy export powerhouse

    How US could turn Pakistan into an energy export powerhouse

    Pakistan stands at a pivotal juncture in its energy journey, where persistent dependence on imported oil and gas collides with the promise of untapped domestic resources.

    New discoveries, seismic surveys and growing international interest point to opportunities to reduce import reliance and enhance long-term energy security. At the same time, policymakers and industry leaders are exploring ways to channel investment into local resources while forging global partnerships to unlock this promise.

    As of December 2024, Pakistan’s proven oil reserves were at approximately 238 million barrels, representing a 23% increase from around 193 million barrels in December 2023.

    Though modest by global standards, the rise highlights the country’s latent potential and the need for sustained investment in domestic exploration. Despite this encouraging rise, domestic production still falls short of meeting national demand, leaving Pakistan heavily reliant on imports to fuel its industries, transport and households.

    The cost of this reliance is steep. In FY2023–24, Pakistan’s petroleum import bill reached US$15.16 billion, according to the State Bank of Pakistan, with some estimates placing it as high as $16.91 billion.

    This ongoing outflow of foreign exchange underscores why developing local reserves remain an urgent priority. Every barrel produced domestically represents not just a saving in import costs but also is a step toward greater national resilience.

    Beyond conventional oil and gas, Pakistan ranks among the world’s most promising nations in terms of shale energy potential. According to the US Energy Information Administration (EIA), Pakistan may hold up to 9 billion barrels of technically recoverable shale oil and around 105 trillion cubic feet of shale gas, mostly in the Sembar and Ranikot formations of the Lower Indus Basin. If developed, these resources could transform Pakistan’s energy landscape.

    However, these figures represent geological potential, not proven reserves. Unlocking them would require substantial drilling, advanced technologies and a carefully phased development strategy. Industry estimates suggest a minimum $5 billion initial investment and several years of groundwork would be needed before commercial-scale extraction is viable.

    This challenge, though formidable, presents an opportunity. Pakistan could leverage partnerships with technologically advanced countries and multinational energy firms to access the expertise, capital and innovation required to realize these untapped resources. Positioning itself as a favorable investment destination could set the stage for a major energy sector transformation.

    The Pakistan-US investment relationship remains underutilized, particularly in sectors such as energy, IT, agriculture, and minerals. Pakistan’s mineral wealth—valued between $6–8 trillion—includes copper, lithium, and rare earths, which are critical to the US clean energy transition and technological competitiveness.

    The Special Investment Facilitation Council (SIFC) has played a key role in streamlining procedures and encouraging investment, especially in renewables and mining. Expanding US FDI in energy and minerals is not just economically sound—it’s strategically imperative for both nations.

    Momentum is also building offshore. A multi-year seismic survey in early 2024 identified promising hydrocarbon structures in the offshore Indus Basin.

    Although early-stage, these findings suggest Pakistan’s coastal regions may hold the key to future discoveries. Successful offshore exploration would not only diversify the energy mix but also elevate Pakistan’s role as a serious player in the global energy markets.

    These developments highlight that Pakistan is not resource-poor—it is resource-underdeveloped. With the right strategy and partnerships, the country could convert geological promise into economic strength, supporting industrial growth, job creation and balance-of-payments stability.

    Energy development must be viewed in the broader context of international partnerships. Since achieving independence in 1947, Pakistan’s relations with the US have weathered geopolitical shifts, yet maintained resilient trade and investment. Today, the U.S. remains Pakistan’s largest export market—accounting for around 17% of exports—and a key source of FDI.

    American firms have invested in Pakistan’s consumer goods, ICT, renewables and financial services, bringing global expertise while creating local opportunities. In return, Pakistan exports textiles, apparel and a growing array of goods, making the US-Pakistan bilateral trade corridor one of South Asia’s most important.

    In July–August 2025, high-level talks led to a new trade agreement focused on developing Pakistan’s oil reserves and reducing bilateral tariffs. The pact aims to deepen cooperation in hydrocarbons and expand market access for Pakistani exports.

    US President Donald Trump even suggested future exploration could position Pakistan as a regional energy exporter—an ambitious yet symbolic endorsement of Pakistan’s potential.

    Pakistan’s energy challenge is real—but so too is its potential. With rising proven reserves, vast shale prospects and promising offshore surveys, the nation stands on the cusp of transformation. Reform, innovation and foreign investment will be key to turning that promise into performance.

    For partners like the US, deeper engagement in Pakistan’s energy sector is both a strategic and economic opportunity that could help undergird regional stability. If managed effectively, Pakistan could shift from chronic energy dependence to become a resilient, self-sufficient player in the global energy market.

    Abubakar Iqbal Sheikh works at a multinational oil and gas drilling company.

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  • Gerard Depardieu ordered to stand trial for rape — lawyer – DW – 09/02/2025

    Gerard Depardieu ordered to stand trial for rape — lawyer – DW – 09/02/2025

    A French judge on Tuesday ordered actor Gerard Depardieu to stand trial on charges of rape and sexual assault, the plaintiff and her lawyer said.

    Depardieu is accused of raping and sexually assaulting actor Charlotte Arnould in 2018, her lawyer, Carine Durrieu Diebolt, was cited by the AFP news agency as saying.

    Arnould said in a post on Instagram that she was “relieved” by the court’s decision to hold a trial.

    “I think I’m having trouble realizing how huge this is. I’m relieved,” she said, adding she had gone through “seven years of horror and hell.”

    Depardieu has denied the allegations.

    The 76-year-old has acted in over 200 films and televisions series.

    Some 20 women have accused Depardieu of inappropriate conduct. He is one of the most high-profile French figures to be accused in the #MeToo movement.

    In May, Depardieu was handed an 18-month suspended sentence after he was convicted of sexual assault for groping two women on a film set in 2021.

    This is a developing news story. Please refresh the page for updates.

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  • Toyota GR Supra selected as official pace car for 2025 NASA Championships

    Toyota GR Supra selected as official pace car for 2025 NASA Championships

    The Toyota GR Supra has been chosen to be the official pace car for the 2025 National Auto Sport Association (NASA) Championships. It will be the third GR Sports car to carry out the duties for NASA’s Nationals.

    Under the hood, is a 3.0-liter inline-six, twin-scroll, turbocharged engine producing 382hp and 368lb-ft of torque. Finished in a bold Toyota Gazoo Racing livery of red, white and black, the GR Supra will lead the field at the National Auto Sport Association’s (NASA) marquee annual event.

    “At Toyota, our passion for performance and motorsports runs deep, and we’re honored to support grassroots racing through our relationship with NASA,” said Mike Tripp, group vice president, Toyota Marketing at Toyota North America. “We’re especially proud to have the GR Supra pacing the 2025 Championships at Ozarks International Raceway — marking its debut as the official NASA Champs pace car.”

    The 2026 model year will mark the final production run of the GR Supra, available in 3.0, 3.0 Premium and MkV Final Edition trims, and all offered with a choice of 6-speed manual or 8-speed automatic transmission.

    The limited-run 2026 GR Supra MkV Final Edition will see only 1,300 units in North America. Offered in red, black and white, the MkV Final Edition features a GT4-Style package with matte-finish paint, race-inspired graphics, carbon fiber red mirror caps, dual stainless steel exhaust tips and a carbon-fiber ducktail spoiler.

    “The relationship between Toyota and NASA has been an incredible way to introduce sports car owners to the world of performance driving in a safe and responsible manner,” said Jeremy Croiset, chief executive officer of NASA. “We’re especially excited to welcome the GR Supra for the first time as the official pace car for the 2025 NASA Championships at Ozarks International Raceway.”

    The event will take place on September 4 to 7, 2025, at Ozarks International Raceway in Gravois Mills, Missouri.

    In related news, Ram has confirmed that Kaulig Racing will become the anchor factory team for the truck maker’s anticipated return to NASCAR, starting with the NASCAR Craftsman Truck Series in 2026

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  • Common diabetes drug metformin may alter metal amounts in blood, study finds

    Common diabetes drug metformin may alter metal amounts in blood, study finds

    Clinical trials and experiments in animals are needed to discern cause-and-effect links between how metformin works and the effects it produces, findings from which could help in developing new drugs, the team said |Photograph used for representational purpose only
    | Photo Credit: Getty Images

    Metformin, a commonly prescribed anti-diabetic drug, could impact metal levels in blood by significantly lowering copper and iron and spiking zinc amounts, possibly related to preventing complications, according to a study.

    The drug helps one manage diabetes by lowering blood sugar levels.

    The findings, published in the British Medical Journal (BMJ) Open Diabetes Research and Care, are an important step in understanding how the common anti-diabetes drug works, researchers said.

    “It is significant that we could show this in humans. Furthermore, since decreases in copper and iron concentrations and an increase in zinc concentration are all considered to be associated with improved glucose tolerance and prevention of complications, these changes may indeed be related to metformin’s action,” author Wataru Ogawa, an endocrinologist and professor at Japan’s Kobe University, said.

    Among nearly 200 diabetes patients at the at Kobe University Hospital — half of whom took metformin for at least six months and half did not — samples of blood serum were analysed for copper, iron and zinc, along with substances that might indicate metal deficiency.

    “Metformin users showed significantly lower serum copper and iron levels, and higher zinc levels, compared to the non-users,” the authors wrote.

    Further, the lowered copper and iron measures were found to be in line with deficiencies of the metals.

    The changes in metal amounts in blood could be related to the effects produced in the body due to metformin, which also include benefits such as action against tumours and inflammation, the authors added.

    “It is known that diabetes patients experience changes in the blood levels of metals such as copper, iron and zinc. In addition, chemical studies found that metformin has the ability to bind certain metals, such as copper, and recent studies showed that it is this binding ability that might be responsible for some of the drug’s beneficial effects,” Ogawa said.

    “So, we wanted to know whether metformin actually affects blood metal levels in humans, which had not been clarified,” the author said.

    Clinical trials and experiments in animals are needed to discern cause-and-effect links between how metformin works and the effects it produces, findings from which could help in developing new drugs, the team said.

    Published – September 02, 2025 05:03 pm IST

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  • Microplastics can trigger Alzheimer’s-like symptoms in mice, study shows – The Washington Post

    1. Microplastics can trigger Alzheimer’s-like symptoms in mice, study shows  The Washington Post
    2. Nanoplastics Might Speed Up Brain Decline, Scientists Say  yahoo.com
    3. Nanoplastics Linked to Brain Decline in New Alzheimer’s Study  Men’s Journal
    4. Scientists issue warning on overlooked factor that could exacerbate Alzheimer’s: ‘Spreads from the top down’  yahoo.com

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  • Strasbourg sign England’s Chilwell from Chelsea

    Strasbourg sign England’s Chilwell from Chelsea


    STRASBOURG:

    England international full-back Ben Chilwell has joined Strasbourg from Chelsea on a two-year deal, the French club announced late on Monday.

    No details of a fee were revealed by Strasbourg, who are owned by the same BlueCo consortium that runs Chelsea.

    Chilwell, who is 28, had been at Stamford Bridge since 2020 and played in the team that won the Champions League the following year.

    However, he gradually fell out of favour and made just one appearance last season before finishing the campaign on loan at Crystal Palace, for whom he featured on their triumphant FA Cup run.

    The former Leicester City defender could now come up against Palace with the sides drawn to face each other in this season’s UEFA Conference League.

    Chilwell has won 21 caps for England but none since March of last year.

    At Strasbourg he will play under English coach Liam Rosenior and will be a teammate of several players who have come from Chelsea.

    The Ligue 1 side signed young French midfielder Mathis Amougou from the Stamford Bridge club during the summer, as well as young full-back Ishe Samuels-Smith.

    Goalkeeper Mike Penders and Ecuador starlet Kendry Paez moved from Chelsea to Alsace on loan, while Mamadou Sarr was bought by the Premier League team from Strasbourg before being loaned back.

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  • Sweden's Klarna seeks up to $14 billion valuation in long-awaited US IPO – Reuters

    1. Sweden’s Klarna seeks up to $14 billion valuation in long-awaited US IPO  Reuters
    2. Klarna aims to raise up to $1.27 billion in U.S. IPO  CNBC
    3. Swedish fintech Klarna aims to raise $1.27 billion in long-awaited IPO  MarketScreener
    4. Klarna, Backers Seek $1.27 Billion in US IPO After Tariff Pause  Bloomberg
    5. Klarna Resumes IPO Filing After Pause Earlier This Year  FinTech Magazine

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  • Google Pixel 10 Pro vs. iPhone 16 Pro: I’ve tried both flagships, and there’s an easy winner

    Google Pixel 10 Pro vs. iPhone 16 Pro: I’ve tried both flagships, and there’s an easy winner

    Kerry Wan/ZDNET

    After the success of launching four flagship phones last year, Google is set to continue the trend with the new Pixel 10 series.

    The Google Pixel 10 Pro stands out as potentially the best option for many people. With a starting price of $999, it offers a compelling blend of premium features borrowed from its more expensive sibling, all in the more manageable size of the standard Pixel 10.

    Also: I replaced my Samsung Galaxy S25 Ultra with the Pixel 10 Pro XL for a week – and can’t go back

    The Pixel 10 Pro enters a crowded field, competing directly with the iPhone 16 Pro and the Galaxy S25 Plus.

    Having used the iPhone 16 Pro as my daily driver for the past year, I’ve tested it against the new Pixel 10 Pro to see how these two flagship phones compare.

    You should buy the Google Pixel 10 Pro if…

    EMBARGO - Google Pixel 10 Pro

    Joseph Maldonado/ZDNET

    1. You want the best of Google AI

    The Pixel phone lineup unsurprisingly offers the best of Google’s Gemini AI features. And it is only getting better with the Pixel 10 Pro. The company is providing a year of Google AI Pro service for free alongside the purchase for Pixel 10 Pro and Pixel 10 Pro XL. So, you get Gemini Pro, including NotebookLM for productivity and Veo 3 text-to-video generation model. 

    The Google Pixel 10 Pro is also getting a contextual and personalized AI feature called Magic Cue. Theoretically, it can “help connect the dots across your digital life by anticipating your needs and proactively suggesting relevant information and helpful actions based on the context on your phone.” 

    Also: The best Android phones to buy in 2025

    For instance, if you call a company’s helpline, your associated details (like a flight ticket) will be surfaced automatically. 

    You can still download the Gemini app to access Google’s AI on your iPhone, but you won’t get the seamless Pixel AI experience. If you depend on Google apps to get work done and have all your digital life stored on Google’s platforms, the Pixel 10 Pro is the better option.

    2. You want a better telephoto camera

    The Google Pixel 10 Pro features a 48MP Quad PD telephoto camera with 5x optical zoom, as compared to a 12MP telephoto sensor (also 5x optical zoom) on the iPhone 16 Pro. However, megapixels don’t solely define a camera. The Pixel 10 Pro sports a bigger sensor than its Apple counterpart. On paper, it is capable of letting more light in and snapping better-looking photos.

    Also: I replaced my Pixel 9 Pro with the 9a for a month – here’s my buying advice now

    The 12MP 5x tele camera on iPhone 16 Pro isn’t hard to beat. It struggles in anything less than bright daylight and lacks the zoom capabilities of its Chinese rivals. I’m looking forward to using the Google Pixel 10 Pro for my zoom shots and expect it to beat the iPhone.

    3. You want a cool-looking Pro phone

    The iPhone 16 Pro series is lacking in fun colors. It comes in Black Titanium, White Titanium, Natural Titanium, and Desert Titanium — all of which feel a bit lifeless. The last Pro iPhone color I truly loved was Sierra Blue on my iPhone 13 Pro Max. 

    While rumors suggest the iPhone 17 Pro might bring back more playful finishes, Google has already beaten Apple to the punch with the Pixel 10 Pro series. The new Pixel 10 and Pixel 10 Pro are available in classic Obsidian and Porcelain, as well as bolder Moonstone and Jade options. 

    So, if you’re spending $1,000 on a phone, you don’t have to settle for something dull. Plus, you get Google’s distinct design, complete with the iconic camera bar—which, in my opinion, still looks incredibly cool.

    4. If you’ve been envious of this iPhone feature

    The Pixel 10 Pro features a MagSafe-like feature called PixelSnap. It is based on Qi2 charging, which offers magnetic accessory support for power banks, chargers, and more. If you’ve been on the iPhone for a while and want to switch platforms, this is the best time to come to the Android side. 

    Also: How to add MagSafe to your Android phone (and why you’ll love it)

    All your MagSafe accessories should technically work with the Pixel 10 Pro (depending on magnet power), so you don’t have to buy new accessories alongside your new phone.

    You should buy the Apple iPhone 16 Pro if…

    iPhone 16 Pro in Dessert Titanium

    Sabrina Ortiz/ZDNET

    1. You want a lighter Pro phone

    The Google Pixel 10 Pro might look better on paper, but it’s nearly 10 grams heavier than the iPhone 16 Pro. Specifically, the Pixel weighs 207 grams compared to the iPhone’s 199 grams.

    Also: Buy the iPhone 16 or wait for iPhone 17? Here’s how I help friends and family decide

    That eight-gram difference might not seem like much, but with both phones featuring flat, unergonomic sides, every gram counts — especially during extended use. If you average more than six hours of screen time a day, the iPhone 16 Pro could be the more comfortable choice.

    2. You want the best social media experience

    While Android has made significant progress, iPhones still hold an advantage in stability and app optimization. This is particularly noticeable with social media apps like X and Instagram, where the user experience remains smoother on Apple devices. 

    Editing and posting photos and videos from an iPhone to social media platforms is also more seamless and efficient for anyone who regularly creates content.

    Also: Best iPhone 2025: I tested the top models and found the best options for you

    If you’re leaning toward an iPhone instead of the Pixel 10 Pro, I strongly recommend waiting just a few weeks. Apple is expected to launch its new iPhone 17 series in early September. It’s smart to hold off on your decision until after the typical September 10th launch event to make sure you get the latest model.


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