{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:58Z","timestamp":1785422758331,"version":"3.56.0"},"reference-count":65,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"NIH NIDDK","doi-asserted-by":"publisher","award":["R01 DK123264"],"award-info":[{"award-number":["R01 DK123264"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008231","name":"Arkansas Bioscience Institute","doi-asserted-by":"crossref","award":["037122"],"award-info":[{"award-number":["037122"]}],"id":[{"id":"10.13039\/100008231","id-type":"DOI","asserted-by":"crossref"}]},{"award":["037122"],"award-info":[{"award-number":["037122"]}],"id":[{"id":"https:\/\/ror.org\/04ptmx344","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa\/fa and lean Fa\/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease.<\/jats:p>","DOI":"10.3390\/nu18132061","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T01:03:56Z","timestamp":1782349436000},"page":"2061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired Renal Mitochondria and Bioenergetics During Obesity-Associated NAFLD"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2860-7790","authenticated-orcid":false,"given":"Amod","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4829-8478","authenticated-orcid":false,"given":"Reza","family":"Hakkak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"},{"name":"Arkansas Children\u2019s Research Institute, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0595-4367","authenticated-orcid":false,"given":"Shannon","family":"Rose","sequence":"additional","affiliation":[{"name":"Department of Health Promotion and Disease Prevention, College of Nursing, The University of Tennessee Health Science Center, Memphis, TN 38103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neriman","family":"Gokden","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3994-5338","authenticated-orcid":false,"given":"Nirmala","family":"Parajuli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S2468-1253(22)00165-0","article-title":"The Prevalence and Incidence of NAFLD Worldwide: A Systematic Review and Meta-Analysis","volume":"7","author":"Riazi","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1136\/gutjnl-2020-323082","article-title":"Non-Alcoholic Fatty Liver Disease and Risk of Incident Chronic Kidney Disease: An Updated Meta-Analysis","volume":"71","author":"Mantovani","year":"2022","journal-title":"Gut"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s40001-023-01114-6","article-title":"Non-Alcoholic Fatty Liver Disease (NAFLD) Is Associated with an Increased Incidence of Chronic Kidney Disease (CKD)","volume":"28","author":"Roderburg","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhang, M., Lin, S., Wang, M., Huang, J., Liu, S., Wu, S., Zhang, H., Wu, Z., Liu, W.-Y., and Zhang, D.-C. (2020). Association between NAFLD and Risk of Prevalent Chronic Kidney Disease: Why There Is a Difference between East and West?. BMC Gastroenterol., 20.","DOI":"10.1186\/s12876-020-01278-z"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sharma, A., Hakkak, R., Gokden, N., Joshi, N., and Parajuli, N. (2025). Obesity-Associated NAFLD Coexists with a Chronic Inflammatory Kidney Condition That Is Partially Mitigated by Short-Term Oral Metformin. Nutrients, 17.","DOI":"10.3390\/nu17132115"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1681\/ASN.2008070759","article-title":"Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments","volume":"20","author":"Hall","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nrneph.2017.107","article-title":"Mitochondrial Energetics in the Kidney","volume":"13","author":"Bhargava","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nm.3762","article-title":"Defective Fatty Acid Oxidation in Renal Tubular Epithelial Cells Has a Key Role in Kidney Fibrosis Development","volume":"21","author":"Kang","year":"2015","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"C333","DOI":"10.1152\/ajpcell.1989.257.2.C333","article-title":"Glycolytic and Oxidative Metabolism in Primary Renal Proximal Tubule Cultures","volume":"257","author":"Dickman","year":"1989","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.5115\/acb.2016.49.2.79","article-title":"Poly(ADP-Ribose) Polymerase Regulates Glycolytic Activity in Kidney Proximal Tubule Epithelial Cells","volume":"49","author":"Song","year":"2016","journal-title":"Anat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"118116","DOI":"10.1016\/j.lfs.2020.118116","article-title":"Quercetin Alleviates Kidney Fibrosis by Reducing Renal Tubular Epithelial Cell Senescence through the SIRT1\/PINK1\/Mitophagy Axis","volume":"257","author":"Liu","year":"2020","journal-title":"Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101957","DOI":"10.1016\/j.mito.2024.101957","article-title":"The Multifaceted Effects of Mitochondria in Kidney Diseases","volume":"79","author":"Xue","year":"2024","journal-title":"Mitochondrion"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cui, J., Shi, S., Sun, X., Cai, G., Cui, S., Hong, Q., Chen, X., and Bai, X.-Y. (2013). Mitochondrial Autophagy Involving Renal Injury and Aging Is Modulated by Caloric Intake in Aged Rat Kidneys. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069720"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1172\/JCI37829","article-title":"Regulation of Mitochondrial Dynamics in Acute Kidney Injury in Cell Culture and Rodent Models","volume":"119","author":"Brooks","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1016\/S0021-9258(19)73804-6","article-title":"Studies on the Electron Transfer System","volume":"237","author":"Hatefi","year":"1962","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/212257a0","article-title":"Synthesis of Adenosine Triphosphate by a Protonmotive Force in Rat Liver Mitochondria","volume":"212","author":"Reid","year":"1966","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-9861(77)90035-2","article-title":"Production of Superoxide Radicals and Hydrogen Peroxide by NADH-Ubiquinone Reductase and Ubiquinol-Cytochrome c Reductase from Beef-Heart Mitochondria","volume":"180","author":"Cadenas","year":"1977","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27103","DOI":"10.1074\/jbc.M111.252502","article-title":"Evidence for Two Sites of Superoxide Production by Mitochondrial NADH-Ubiquinone Oxidoreductase (Complex I)","volume":"286","author":"Treberg","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/0003-9861(85)90293-0","article-title":"Ubisemiquinone Is the Electron Donor for Superoxide Formation by Complex III of Heart Mitochondria","volume":"237","author":"Turrens","year":"1985","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E1047","DOI":"10.1152\/ajpendo.00666.2010","article-title":"High-Fat Diet Induces an Initial Adaptation of Mitochondrial Bioenergetics in the Kidney despite Evident Oxidative Stress and Mitochondrial ROS Production","volume":"300","author":"Ruggiero","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112635","DOI":"10.1016\/j.mce.2025.112635","article-title":"Mitochondrial Dysfunction and Defective Quality Control Mechanisms in the Kidney Are Not Reversed by High-Fat Diet Withdrawal in Early Obese Mice","volume":"608","author":"Braga","year":"2025","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.tcb.2022.03.012","article-title":"The Multifaceted Role of Kidney Tubule Mitochondrial Dysfunction in Kidney Disease Development","volume":"32","author":"Doke","year":"2022","journal-title":"Trends Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F941","DOI":"10.1152\/ajprenal.00203.2019","article-title":"Obesity Causes Renal Mitochondrial Dysfunction and Energy Imbalance and Accelerates Chronic Kidney Disease in Mice","volume":"317","author":"Lanaspa","year":"2019","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/s41419-020-03122-4","article-title":"High-Fat Diet Promotes Renal Injury by Inducing Oxidative Stress and Mitochondrial Dysfunction","volume":"11","author":"Sun","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bbadis.2016.11.010","article-title":"Mitochondrial Dysfunction and Oxidative Stress in Metabolic Disorders\u2014A Step towards Mitochondria Based Therapeutic Strategies","volume":"1863","author":"Bhatti","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.molcel.2023.02.012","article-title":"Determinants and Outcomes of Mitochondrial Dynamics","volume":"83","author":"Scorrano","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s42255-024-00978-0","article-title":"Obesity Causes Mitochondrial Fragmentation and Dysfunction in White Adipocytes Due to RalA Activation","volume":"6","author":"Xia","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3399","DOI":"10.1038\/s41467-018-05655-x","article-title":"The Cristae Modulator Optic Atrophy 1 Requires Mitochondrial ATP Synthase Oligomers to Safeguard Mitochondrial Function","volume":"9","author":"Quirin","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.cmet.2015.05.007","article-title":"The OPA1-Dependent Mitochondrial Cristae Remodeling Pathway Controls Atrophic, Apoptotic, and Ischemic Tissue Damage","volume":"21","author":"Varanita","year":"2015","journal-title":"Cell Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1530\/EC-19-0234","article-title":"Increased Mitochondrial Fission of Glomerular Podocytes in Diabetic Nephropathy","volume":"8","author":"Ma","year":"2019","journal-title":"Endocr. Connect."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/emboj\/17.1.37","article-title":"Mitochondrial Cytochrome c Release in Apoptosis Occurs Upstream of DEVD-Specific Caspase Activation and Independently of Mitochondrial Transmembrane Depolarization","volume":"17","year":"1998","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3892\/br.2021.1425","article-title":"Effects of Obesity and 10 Weeks Metformin Treatment on Liver Steatosis","volume":"14","author":"Hakkak","year":"2021","journal-title":"BioMed Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1038\/79697","article-title":"Metformin Reverses Fatty Liver Disease in Obese, Leptin-Deficient Mice","volume":"6","author":"Lin","year":"2000","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.bbrc.2010.04.017","article-title":"Metformin Reduces Intracellular Reactive Oxygen Species Levels by Upregulating Expression of the Antioxidant Thioredoxin via the AMPK-FOXO3 Pathway","volume":"396","author":"Hou","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1126\/science.aab4138","article-title":"AMP-Activated Protein Kinase Mediates Mitochondrial Fission in Response to Energy Stress","volume":"351","author":"Toyama","year":"2016","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1042\/bj3480607","article-title":"Evidence That Metformin Exerts Its Anti-Diabetic Effects through Inhibition of Complex 1 of the Mitochondrial Respiratory Chain","volume":"348","author":"Owen","year":"2000","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Melnyk, S., and Hakkak, R. (2023). Effect of Metformin Treatment on Serum Metabolic Profile Changes in Lean and Obese Zucker Rat Model for Fatty Liver Disease. Biomolecules, 13.","DOI":"10.3390\/biom13081234"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Melnyk, S., and Hakkak, R. (2022). Metabolic Status of Lean and Obese Zucker Rats Based on Untargeted and Targeted Metabolomics Analysis of Serum. Biomedicines, 10.","DOI":"10.3390\/biomedicines10010153"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1097\/TP.0000000000005310","article-title":"Cold Storage Disrupts the Proteome and Phosphoproteome Landscape in Rat Kidney Transplants","volume":"109","author":"Sharma","year":"2025","journal-title":"Transplantation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e454","DOI":"10.1097\/TXD.0000000000000897","article-title":"Cold Storage Increases Albumin and Advanced Glycation-End Product-Albumin Levels in Kidney Transplants: A Possible Cause for Exacerbated Renal Damage","volume":"5","author":"Lo","year":"2019","journal-title":"Transpl. Direct"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/nprot.2006.62","article-title":"Blue Native PAGE","volume":"1","author":"Wittig","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"49064","DOI":"10.1074\/jbc.M407715200","article-title":"Complex III Releases Superoxide to Both Sides of the Inner Mitochondrial Membrane","volume":"279","author":"Muller","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"16330","DOI":"10.1016\/S0021-9258(17)46227-2","article-title":"The Oxidative Inactivation of Mitochondrial Electron Transport Chain Components and ATPase","volume":"265","author":"Zhang","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"152919","DOI":"10.1016\/j.bbrc.2025.152919","article-title":"PKA-Mediated Drp1 Ser637 Phosphorylation Modulates Mitochondrial Function in the Placenta of Gestational Diabetes Mellitus","volume":"790","author":"Shi","year":"2025","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7115","DOI":"10.1074\/jbc.M116.762567","article-title":"The Short Variant of the Mitochondrial Dynamin OPA1 Maintains Mitochondrial Energetics and Cristae Structure","volume":"292","author":"Lee","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"103760","DOI":"10.1016\/j.redox.2025.103760","article-title":"Obesity-Induced Arterial Redox Imbalance Involving Mitochondrial NOX4, Endothelial Dysfunction, and ER Stress Underlie Kidney Injury Compensated by Enhanced Mitochondrial Bioenergetics","volume":"85","author":"Contreras","year":"2025","journal-title":"Redox Biol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ramanathan, R., Ali, A.H., and Ibdah, J.A. (2022). Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137280"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101134","DOI":"10.1016\/j.molmet.2020.101134","article-title":"Mitochondrial Oxidative Function in NAFLD: Friend or Foe?","volume":"50","author":"Shum","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"16082","DOI":"10.1038\/s41598-017-16463-6","article-title":"Increased Inflammation, Oxidative Stress and Mitochondrial Respiration in Brown Adipose Tissue from Obese Mice","volume":"7","author":"Bustos","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.bbabio.2012.12.002","article-title":"Superoxide Generation by Complex III: From Mechanistic Rationales to Functional Consequences","volume":"1827","author":"Bleier","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.2337\/db22-0728","article-title":"A Defect in Mitochondrial Complex III but Not in Complexes I or IV Causes Early \u03b2-Cell Dysfunction and Hyperglycemia in Mice","volume":"72","author":"Lang","year":"2023","journal-title":"Diabetes"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.febslet.2011.04.004","article-title":"Mitochondrial Consumption of Cytosolic ATP: Not so Fast","volume":"585","author":"Chinopoulos","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_54","first-page":"789","article-title":"Mitochondrial Dysfunction Results from Oxidative Stress in the Skeletal Muscle of Diet-Induced Insulin-Resistant Mice","volume":"118","author":"Bonnard","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1172\/JCI66218","article-title":"AMPK Dysregulation Promotes Diabetes-Related Reduction of Superoxide and Mitochondrial Function","volume":"123","author":"Dugan","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1177\/15353702231191178","article-title":"Metformin Inhibits Mitochondrial Dysfunction and Apoptosis in Cardiomyocytes Induced by High Glucose via Upregulating AMPK Activity","volume":"248","author":"Wu","year":"2023","journal-title":"Exp. Biol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/j.celrep.2019.09.070","article-title":"Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK","volume":"29","author":"Wang","year":"2019","journal-title":"Cell Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From Mechanisms of Action to Therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cmet.2008.06.001","article-title":"Regulation of Mitochondrial Structure and Function by the F1Fo-ATPase Inhibitor Protein, IF1","volume":"8","author":"Campanella","year":"2008","journal-title":"Cell Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/j.bbabio.2016.02.004","article-title":"The ATPase Inhibitory Factor 1 (IF1): A Master Regulator of Energy Metabolism and of Cell Survival","volume":"1857","author":"Cuezva","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1016\/j.celrep.2017.01.070","article-title":"Control of Mitochondrial Remodeling by the ATPase Inhibitory Factor 1 Unveils a Pro-Survival Relay via OPA1","volume":"18","author":"Faccenda","year":"2017","journal-title":"Cell Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.redox.2017.01.013","article-title":"Mitochondrial Dynamics in Type 2 Diabetes: Pathophysiological Implications","volume":"11","author":"Rocha","year":"2017","journal-title":"Redox Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41419-019-2218-5","article-title":"Drp1-Mediated Mitochondrial Fission Promotes Renal Fibroblast Activation and Fibrogenesis","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nrneph.2018.9","article-title":"Mitochondrial Dysfunction in Diabetic Kidney Disease","volume":"14","author":"Forbes","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Dai, W., and Jiang, L. (2019). Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00570"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/13\/2061\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:53:19Z","timestamp":1782535999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/13\/2061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":65,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["nu18132061"],"URL":"https:\/\/doi.org\/10.3390\/nu18132061","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]}}}