Mitochondrial quality control mechanisms as molecular targets in diabetic heart

Published:September 16, 2022DOI:


      • Mitochondrial dysfunction can induce or aggravate pathological alterations of the diabetic heart.
      • Physiological MQC is an endogenous defense program that restores the mitochondrial integrity.
      • Mitochondrial fission is overactivated in diabetic hearts, while fusion is markedly inhibited.
      • Mitophagy can engulf fragmented mitochondria; however, this process is inhibited under hyperglycemia.


      Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.

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        • Kannel W.B.
        • Hjortland M.
        • Castelli W.P.
        Role of diabetes in congestive heart failure: the Framingham study.
        Am J Cardiol. 1974; 34: 29-34
        • Regan T.J.
        • Lyons M.M.
        • Ahmed S.S.
        • et al.
        Evidence for cardiomyopathy in familial diabetes mellitus.
        J Clin Invest. 1977; 60: 885-899
        • Rubler S.
        • Dlugash J.
        • Yuceoglu Y.Z.
        • Kumral T.
        • Branwood A.W.
        • Grishman A.
        New type of cardiomyopathy associated with diabetic glomerulosclerosis.
        Am J Cardiol. 1972; 30: 595-602
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        2013 ACCF/AHA guideline for the management of heart failure a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        J Am Coll Cardiol. 2013; 62: e147-e239
        • Members A.F.
        • Rydén L.
        • Grant P.J.
        • et al.
        ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASDThe Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD).
        Eur Heart J. 2013; 34: 3035-3087
        • Dandamudi S.
        • Slusser J.
        • Mahoney D.W.
        • Redfield M.M.
        • Rodeheffer R.J.
        • Chen H.H.
        The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County,Minnesota.
        J Card Fail. 2014; 20: 304-309
        • Galderisi M.
        Diastolic dysfunction and diastolic heart failure: diagnostic, prognostic and therapeutic aspects.
        Cardiovasc Ultrasoun. 2005; 3 (9-9)
        • Gottlieb I.
        • Macedo R.
        • Bluemke D.A.
        • Lima J.A.C.
        Magnetic resonance imaging in the evaluation of non-ischemic cardiomyopathies: current applications and future perspectives.
        Heart Fail Rev. 2006; 11: 313-323
        • Redfield M.M.
        • Jacobsen S.J.
        • Burnett J.J.C.
        • Mahoney D.W.
        • Bailey K.R.
        • Rodeheffer R.J.
        Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.
        JAMA. 2003; 289: 194-202
        • Fang Z.Y.
        • Prins J.B.
        • Marwick T.H.
        Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications.
        Endocr Rev. 2004; 25: 543-567
        • Li S.
        • Dong S.
        • Shi B.
        • et al.
        Attenuation of ROS/chloride efflux-mediated NLRP3 inflammasome activation contributes to alleviation of diabetic cardiomyopathy in rats after sleeve gastrectomy.
        Oxid Med Cell Longev. 2022; 20224608914
        • Zhong X.
        • Wang T.
        • Zhang W.
        • et al.
        ERK/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1.
        J Biol Chem. 2022; 101989
        • Farazandeh M.
        • Mahmoudabady M.
        • Asghari A.A.
        • Niazmand S.
        Diabetic cardiomyopathy was attenuated by cinnamon treatment through the inhibition of fibro-inflammatory response and ventricular hypertrophy in diabetic rats.
        J Food Biochem. 2022; e14206
        • Wang J.
        • Toan S.
        • Zhou H.
        New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury.
        Angiogenesis. 2020; 23: 299-314
        • Zhu H.
        • Toan S.
        • Mui D.
        • Zhou H.
        Mitochondrial quality surveillance as a therapeutic target in myocardial infarction.
        Acta Physiol. 2021; 231e13590
        • Wang J.
        • Zhou H.
        Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia–reperfusion injury.
        Acta Pharm SinB. 2020; 10: 1866-1879
        • Wang J.
        • Toan S.
        • Zhou H.
        Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: new insights into the mechanisms and therapeutic potentials.
        Pharmacol Res. 2020; 156104771
        • Anderson E.J.
        • Rodriguez E.
        • Anderson C.A.
        • Thayne K.
        • Chitwood W.R.
        • Kypson A.P.
        Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways.
        Am J PhysiolHeart C. 2011; 300: H118-H124
        • Yang Y.
        • Zhao J.
        • Qiu J.
        • et al.
        Xanthine oxidase inhibitor allopurinol prevents oxidative stress-mediated atrial remodeling in alloxan-induced diabetes mellitus rabbits.
        J Am Heart Assoc. 2018; 7e008807
        • Pham T.
        • Loiselle D.
        • Power A.
        • Hickey A.J.R.
        Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart.
        Am J PhysiolCell Physiol. 2014; 307: C499-C507
        • Tocchetti C.G.
        • Caceres V.
        • Stanley B.A.
        • et al.
        GSH or palmitate preserves mitochondrial energetic/redox balance, preventing mechanical dysfunction in metabolically challenged myocytes/hearts from type 2 diabetic mice.
        Diabetes. 2012; 61: 3094-3105
        • Morishima M.
        • Horikawa K.
        • Funaki M.
        Cardiomyocytes cultured on mechanically compliant substrates, but not on conventional culture devices, exhibit prominent mitochondrial dysfunction due to reactive oxygen species and insulin resistance under high glucose.
        Plos One. 2018; 13e0201891
        • Li H.
        • Dai B.
        • Fan J.
        • et al.
        The different roles of miRNA-92a-2-5p and let-7b-5p in mitochondrial translation in db/db mice.
        Mol Ther Nucleic Acids. 2019; 17: 424-435
        • Nakamura H.
        • Matoba S.
        • Iwai-Kanai E.
        • et al.
        p53 promotes cardiac dysfunction in diabetic mellitus caused by excessive mitochondrial respiration-mediated reactive oxygen species generation and lipid accumulation.
        CircHeart Fail. 2012; 5: 106-115
        • Sedlic F.
        • Muravyeva M.Y.
        • Sepac A.
        • et al.
        Targeted modification of mitochondrial ROS production converts high glucose-induced cytotoxicity to cytoprotection: effects on anesthetic preconditioning.
        J Cell Physiol. 2017; 232: 216-224
        • Jeong E.
        • Chung J.
        • Liu H.
        • et al.
        Role of mitochondrial oxidative stress in glucose tolerance, insulin resistance, and cardiac diastolic dysfunction.
        J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2016; 5e003046
        • Ni R.
        • Cao T.
        • Xiong S.
        • et al.
        Therapeutic inhibition of mitochondrial reactive oxygen species with Mito-TEMPO reduces diabetic cardiomyopathy.
        Free Radical Bio Med. 2016; 90: 12-23
        • Saito S.
        • Thuc L.C.
        • Teshima Y.
        • et al.
        Glucose fluctuations aggravate cardiac susceptibility to ischemia/reperfusion injury by modulating microRNAs expression.
        Circ J. 2016; 80: 186-195
        • Roussel J.
        • Thireau J.
        • Brenner C.
        • et al.
        Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: role of adenine nucleotide translocase.
        BiochimBiophysActaMol Basis Dis. 2015; 1852: 749-758
        • He Q.
        • Harris N.
        • Ren J.
        • Han X.
        Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes.
        Oxid Med Cell Longev. 2014; 2014654198
        • Zhou H.
        • Hu S.
        • Jin Q.
        • et al.
        Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening.
        J Am Heart Assoc Cardiovasc Cerebrovasc Dis. 2017; 6e005328
        • Zhu Y.
        • Yang X.
        • Zhou J.
        • et al.
        miR-340-5p mediates cardiomyocyte oxidative stress in diabetes-induced cardiac dysfunction by targeting Mcl-1.
        Oxid Med Cell Longev. 2022; 2022: 3182931
        • Suarez J.
        • Cividini F.
        • Scott B.T.
        • et al.
        Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function.
        J Biol Chem. 2018; 293: 8182-8195
        • Sygitowicz G.
        • Sitkiewicz D.
        Mitochondrial quality control: the role in cardiac injury.
        Front Biosci-Landmrk. 2022; 27: 096
        • Kalkhoran S.B.
        • Kararigas G.
        Oestrogenic regulation of mitochondrial dynamics.
        Int J Mol Sci. 2022; 23: 1118
        • Scheffer D.da L.
        • Garcia A.A.
        • Lee L.
        • Mochly-Rosen D.
        • Ferreira J.C.B.
        Mitochondrial fusion, fission, and mitophagy in cardiac diseases: challenges and therapeutic opportunities.
        Antioxid Redox Sign. 2022; 36: 844-863
        • Song Z.
        • Ghochani M.
        • McCaffery J.M.
        • Frey T.G.
        • Chan D.C.
        Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion.
        Mol Biol Cell. 2009; 20: 3525-3532
        • Casellas-Díaz S.
        • Larramona-Arcas R.
        • Riqué-Pujol G.
        • et al.
        Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.
        EMBO Rep. 2021; 22e51954
        • Meeusen S.
        • DeVay R.
        • Block J.
        • et al.
        Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1.
        Cell. 2006; 127: 383-395
        • Yu C.
        • Zhao J.
        • Yan L.
        • et al.
        Structural insights into G domain dimerization and pathogenic mutation of OPA1.
        J Cell Biol. 2020; 219e201907098
        • Yan L.
        • Qi Y.
        • Ricketson D.
        • et al.
        Structural analysis of a trimeric assembly of the mitochondrial dynamin-like GTPase Mgm1.
        Proc Natl Acad Sci USA. 2020; 117: 4061-4070
        • Anand R.
        • Wai T.
        • Baker M.J.
        • et al.
        The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission.
        J Cell Biol. 2014; 204: 919-929
        • Gilkerson R.
        • Torre P.D.L.
        • Vallier SSt
        Mitochondrial OMA1 and OPA1 as gatekeepers of organellar structure/function and cellular stress response.
        FrontCell Dev Biol. 2021; 9626117
        • Friedman J.R.
        • Lackner L.L.
        • West M.
        • DiBenedetto J.R.
        • Nunnari J.
        • Voeltz G.K.
        ER tubules mark sites of mitochondrial division.
        Science. 2011; 334: 358-362
        • Yang Y.
        • Lei W.
        • Zhao L.
        • Wen Y.
        • Li Z.
        Insights into mitochondrial dynamics in chlamydial infection.
        Front Cell Infect Micorbiol. 2022; 12835181
        • Fröhlich C.
        • Grabiger S.
        • Schwefel D.
        • et al.
        Structural insights into oligomerization and mitochondrial remodelling of dynamin 1-like protein.
        EMBO J. 2013; 32: 1280-1292
        • Jin J.
        • Wei X.
        • Zhi X.
        • Wang X.
        • Meng D.
        Drp1-dependent mitochondrial fission in cardiovascular disease.
        Acta Pharmacol Sin. 2021; 42: 655-664
        • Wang S.
        • Zhu H.
        • Li R.
        • et al.
        DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury.
        Sci Signal. 2022; 15eabh1121
        • Zhou H.
        • Wang J.
        • Zhu P.
        • et al.
        NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α.
        Basic Res Cardiol. 2018; 113: 23
        • Li Y.
        • Chen H.
        • Yang Q.
        • et al.
        Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.
        J Exp Clin Canc Res. 2022; 41: 76
        • Li S.
        • Lin Q.
        • Shao X.
        • et al.
        Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction.
        Free RadicBiol Med. 2020; 152: 632-649
        • Zhou H.
        • Zhang Y.
        • Hu S.
        • et al.
        Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis.
        J Pineal Res. 2017; 63e12413
        • Pereira G.C.
        • Lee L.
        • Rawlings N.
        • et al.
        Hexokinase II dissociation alone cannot account for changes in heart mitochondrial function, morphology and sensitivity to permeability transition pore opening following ischemia.
        Plos One. 2020; 15e0234653
        • Li C.
        • Lin L.
        • Tsai H.
        • Wen Z.
        • Tsui K.
        Phosphoglycerate mutase family member 5 maintains oocyte quality via mitochondrial dynamic rearrangement during aging.
        Aging Cell. 2022; 21e13546
        • Ishihara T.
        • Ban-Ishihara R.
        • Maeda M.
        • et al.
        Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development.
        Mol Cell Biol. 2015; 35: 211-223
        • Song M.
        • Mihara K.
        • Chen Y.
        • Scorrano L.
        • Dorn G.W.
        Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts.
        Cell Metab. 2015; 21: 273-286
        • Montaigne D.
        • Marechal X.
        • Coisne A.
        • et al.
        Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients.
        Circulation. 2014; 130: 554-564
        • Larsen T.D.
        • Sabey K.H.
        • Knutson A.J.
        • 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: 3090
        • Ma T.
        • Huang X.
        • Zheng H.
        • et al.
        SFRP2 improves mitochondrial dynamics and mitochondrial biogenesis, oxidative stress, and apoptosis in diabetic cardiomyopathy.
        Oxid Med Cell Longev. 2021; 20219265016
        • Wu Q.-R.
        • Zheng D.-L.
        • Liu P.-M.
        • et al.
        High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy.
        Cell Death Dis. 2021; 12: 216
        • Feng X.
        • Wang S.
        • Yang X.
        • et al.
        Mst1 knockout alleviates mitochondrial fission and mitigates left ventricular remodeling in the development of diabetic cardiomyopathy.
        FrontCell Dev Biol. 2021; 8628842
        • Ding M.
        • Liu C.
        • Shi R.
        • et al.
        Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1-dependent way.
        Acta Physiol. 2020; 229e13428
        • Ding M.
        • Feng N.
        • Tang D.
        • et al.
        Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway.
        J Pineal Res. 2018; 65e12491
        • Ding M.
        • Dong Q.
        • Liu Z.
        • et al.
        Inhibition of dynamin-related protein 1 protects against myocardial ischemia–reperfusion injury in diabetic mice.
        Cardiovasc Diabetol. 2017; 16: 19
        • Durak A.
        • Olgar Y.
        • Degirmenci S.
        • Akkus E.
        • Tuncay E.
        • Turan B.
        A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats.
        Cardiovasc Diabetol. 2018; 17: 144
        • Zhou H.
        • Wang S.
        • Zhu P.
        • Hu S.
        • Chen Y.
        • Ren J.
        Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission.
        Redox Biol. 2018; 15: 335-346
        • Li W.
        • Ji L.
        • Tian J.
        • et al.
        Ophiopogonin D alleviates diabetic myocardial injuries by regulating mitochondrial dynamics.
        J Ethnopharmacol. 2021; 271113853
        • Chang X.
        • Zhang T.
        • Wang J.
        • et al.
        SIRT5-related desuccinylation modification contributes to quercetin-induced protection against heart failure and high-glucose-prompted cardiomyocytes injured through regulation of mitochondrial quality surveillance.
        Oxid Med Cell Longev. 2021; 20215876841
        • Li A.
        • Gao M.
        • Liu B.
        • et al.
        Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease.
        Cell Death Dis. 2022; 13: 444
        • Liu M.
        • Wu Y.
        Role of mitophagy in coronary heart disease: targeting the mitochondrial dysfunction and inflammatory regulation.
        FrontCardiovasc Med. 2022; 9819454
        • Cox R.T.
        • Poulton J.
        • Williams S.A.
        The role of mitophagy during oocyte aging in human, mouse, and drosophila: implications for oocyte quality and mitochondrial disease.
        ReprodFertil. 2021; 2: R113-R129
        • Diao R.Y.
        • Gustafsson Å.B.
        Mitochondrial quality surveillance: mitophagy in cardiovascular health and disease.
        Am J PhysiolCell Physiol. 2022; 322: C218-C230
        • Kanamori H.
        • Takemura G.
        • Goto K.
        • et al.
        Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes.
        Autophagy. 2015; 11: 1146-1160
        • Kobayashi S.
        • Zhao F.
        • Kobayashi T.
        • et al.
        Hyperglycemia-induced cardiomyocyte death is mediated by lysosomal membrane injury and aberrant expression of cathepsin D.
        Biochem Biophys Res Commun. 2020; 523: 239-245
        • Greene A.W.
        • Grenier K.
        • Aguileta M.A.
        • et al.
        Mitochondrial processing peptidase regulates PINK1 processing, import and parkin recruitment.
        EMBO Rep. 2012; 13: 378-385
        • Narendra D.
        • Tanaka A.
        • Suen D.-F.
        • Youle R.J.
        Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.
        J Cell Biol. 2008; 183: 795-803
        • Kondapalli C.
        • Kazlauskaite A.
        • Zhang N.
        • et al.
        PINK1 is activated by mitochondrial membrane potential depolarization and stimulates parkin E3 ligase activity by phosphorylating serine 65.
        Open Biol. 2012; 2120080
        • Gersch M.
        • Gladkova C.
        • Schubert A.F.
        • Michel M.A.
        • Maslen S.
        • Komander D.
        Mechanism and regulation of the Lys6-selective deubiquitinase USP30.
        Nat Struct Mol Biol. 2017; 24: 920-930
        • Tanaka A.
        • Cleland M.M.
        • Xu S.
        • et al.
        Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by parkin.
        J Cell Biol. 2010; 191: 1367-1380
        • Yoshii S.R.
        • Kishi C.
        • Ishihara N.
        • Mizushima N.
        Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial Membrane* ♦.
        J Biol Chem. 2011; 286: 19630-19640
        • Lazarou M.
        • Sliter D.A.
        • Kane L.A.
        • et al.
        The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.
        Nature. 2015; 524: 309-314
        • Padman B.S.
        • Nguyen T.N.
        • Uoselis L.
        • Skulsuppaisarn M.
        • Nguyen L.K.
        • Lazarou M.
        LC3/GABARAPs drive ubiquitin-independent recruitment of optineurin and NDP52 to amplify mitophagy.
        Nat Commun. 2019; 10: 408
        • Otsu K.
        • Murakawa T.
        • Yamaguchi O.
        BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32.
        Autophagy. 2015; 11: 1932-1933
        • Murakawa T.
        • Yamaguchi O.
        • Hashimoto A.
        • et al.
        Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation.
        Nat Commun. 2015; 6: 7527
        • Chinnadurai G.
        • Vijayalingam S.
        • Gibson S.B.
        BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions.
        Oncogene. 2008; 27: S114-S127
        • Zhu Y.
        • Massen S.
        • Terenzio M.
        • et al.
        Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis*.
        J Biol Chem. 2013; 288: 1099-1113
        • Marinković M.
        • Novak I.
        A brief overview of BNIP3L/NIX receptor-mediated mitophagy.
        FEBS Open Bio. 2021; 11: 3230-3236
        • Ney P.A.
        Mitochondrial autophagy: origins, significance, and role of BNIP3 and NIX.
        BiochimBiophysActaMol Cell Res. 2015; 1853: 2775-2783
        • Zhou H.
        • Zhu P.
        • Wang J.
        • Zhu H.
        • Ren J.
        • Chen Y.
        Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy.
        Cell Death Differ. 2018; 25: 1080-1093
        • Zhou H.
        • Zhu P.
        • Wang J.
        • Toan S.
        • Ren J.
        DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy.
        Signal Transduct Target Ther. 2019; 4: 56
        • Zhou H.
        • Zhu P.
        • Guo J.
        • et al.
        Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury.
        Redox Biol. 2017; 13: 498-507
        • Wang J.
        • Zhu P.
        • Li R.
        • Ren J.
        • Zhou H.
        Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission.
        Redox Biol. 2019; 30101415
        • Wang Y.
        • Jasper H.
        • Toan S.
        • Muid D.
        • Chang X.
        • Zhou H.
        Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury.
        Redox Biol. 2021; 45102049
        • Kobayashi S.
        • Patel J.
        • Zhao F.
        • Huang Y.
        • Kobayashi T.
        • Liang Q.
        Novel dual-fluorescent mitophagy reporter reveals a reduced mitophagy flux in type 1 diabetic mouse heart.
        J Osteopath Med. 2020; 120: 446-455
        • He C.
        • Zhu H.
        • Li H.
        • Zou M.-H.
        • Xie Z.
        Dissociation of Bcl-2–Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes.
        Diabetes. 2013; 62: 1270-1281
        • Wu W.
        • Xu H.
        • Wang Z.
        • et al.
        PINK1-parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury.
        Plos One. 2015; 10e0132499
        • Tong M.
        • Saito T.
        • Zhai P.
        • Oka S.
        • Mizushima W.
        • Nakamura M.
        • et al.
        Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy.
        Circ Res. 2019; 124: 1360-1371
        • 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: 2155-2167
        • Belosludtseva N.V.
        • Starinets V.S.
        • Mikheeva I.B.
        • et al.
        Effect of the MPT pore inhibitor alisporivir on the development of mitochondrial dysfunction in the heart tissue of diabetic mice.
        Biology. 2021; 10: 839
        • Sciarretta S.
        • Zhai P.
        • Shao D.
        • et al.
        Rheb is a critical regulator of autophagy during myocardial ischemia.
        Circulation. 2012; 125: 1134-1146
        • Huang C.-Y.
        • Lai C.-H.
        • Kuo C.-H.
        • et al.
        Inhibition of ERK-Drp1 signaling and mitochondria fragmentation alleviates IGF-IIR-induced mitochondria dysfunction during heart failure.
        J Mol Cell Cardiol. 2018; 122: 58-68
        • Wang S.
        • Zhao Z.
        • Feng X.
        • et al.
        Melatonin activates parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition.
        J Cell Mol Med. 2018; 22: 5132-5144
        • Qiao H.
        • Ren H.
        • Du H.
        • Zhang M.
        • Xiong X.
        • Lv R.
        Liraglutide repairs the infarcted heart: the role of the SIRT1/Parkin/mitophagy pathway.
        Mol Med Rep. 2018; 17: 3722-3734
        • Thai P.N.
        • Miller C.V.
        • King M.T.
        • et al.
        Ketone ester D-β-hydroxybutyrate-(R)-1,3 butanediol prevents decline in cardiac function in type 2 diabetic mice.
        J Am Heart Assoc. 2021; 10e020729
        • Wang J.
        • Chen P.
        • Cao Q.
        • Wang W.
        • Chang X.
        Traditional Chinese medicine Ginseng Dingzhi Decoction ameliorates myocardial fibrosis and high glucose-induced cardiomyocyte injury by regulating intestinal flora and mitochondrial dysfunction.
        Oxid Med Cell Longev. 2022; 20229205908
        • Ongwijitwat S.
        • Wong-Riley M.T.T.
        Is nuclear respiratory factor 2 a master transcriptional coordinator for all ten nuclear-encoded cytochrome c oxidase subunits in neurons?.
        Gene. 2005; 360: 65-77
        • Puigserver P.
        • Wu Z.
        • Park C.W.
        • Graves R.
        • Wright M.
        • Spiegelman B.M.
        A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.
        Cell. 1998; 92: 829-839
        • Barshad G.
        • Marom S.
        • Cohen T.
        • Mishmar D.
        Mitochondrial DNA transcription and its regulation: an evolutionary perspective.
        Trends Genet. 2018; 34: 682-692
        • Wu Z.
        • Puigserver P.
        • Andersson U.
        • et al.
        Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.
        Cell. 1999; 98: 115-124
        • Jäger S.
        • Handschin C.
        • St.-Pierre J.
        • Spiegelman B.M.
        AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α.
        Proc Natl Acad Sci. 2007; 104: 12017-12022
        • Marin T.L.
        • Gongol B.
        • Zhang F.
        • et al.
        AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1.
        Sci Signal. 2017; 10
        • Delghandi M.P.
        • Johannessen M.
        • Moens U.
        The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells.
        Cell Signal. 2005; 17: 1343-1351
        • Herzig S.
        • Long F.
        • Jhala U.S.
        • et al.
        CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.
        Nature. 2001; 413: 179-183
        • Ojuka E.O.
        • Jones T.E.
        • Han D.
        • Chen M.
        • Holloszy J.O.
        Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle.
        FASEB J. 2003; 17: 675-681
        • Wright D.C.
        • Geiger P.C.
        • Han D.-H.
        • Jones T.E.
        • Holloszy J.O.
        Calcium induces increases in peroxisome proliferator-activated receptor γ coactivator-1α and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation*.
        J Biol Chem. 2007; 282: 18793-18799
        • Akimoto T.
        • Pohnert S.C.
        • Li P.
        • et al.
        Exercise stimulates Pgc-1α transcription in skeletal muscle through activation of the p38 MAPK pathway*.
        J Biol Chem. 2005; 280: 19587-19593
        • Handschin C.
        • Rhee J.
        • Lin J.
        • Tarr P.T.
        • Spiegelman B.M.
        An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle.
        Proc NatlAcad Sci. 2003; 100: 7111-7116
        • Gerhart-Hines Z.
        • Rodgers J.T.
        • et al.
        Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α.
        EMBO J. 2007; 26: 1913-1923
        • Yan W.
        • Zhang H.
        • Liu P.
        • et al.
        Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart.
        Basic Res Cardiol. 2013; 108: 329
        • Din S.
        • Konstandin M.H.
        • Johnson B.
        • et al.
        Metabolic dysfunction consistent with premature aging results from deletion of pim kinases.
        Circ Res. 2014; 115: 376-387
        • Ramírez-Sánchez I.
        • Rodríguez A.
        • Moreno-Ulloa A.
        • Ceballos G.
        • Villarreal F.
        (-)-Epicatechin-induced recovery of mitochondria from simulated diabetes: potential role of endothelial nitric oxide synthase.
        DiabVasc Dis Res. 2016; 13: 201-210
        • Glenn D.J.
        • Wang F.
        • Nishimoto M.
        • et al.
        A murine model of isolated cardiac steatosis leads to cardiomyopathy.
        Hypertension. 2011; 57: 216-222
        • Waldman M.
        • Nudelman V.
        • Shainberg A.
        • et al.
        The role of heme oxygenase 1 in the protective effect of caloric restriction against diabetic cardiomyopathy.
        Int J Mol Sci. 2019; 20: 2427
        • Ma S.
        • Feng J.
        • Zhang R.
        • et al.
        SIRT1 activation by resveratrol alleviates cardiac dysfunction via mitochondrial regulation in diabetic cardiomyopathy mice.
        Oxid Med Cell Longev. 2017; 2017: 4602715
        • Zhang M.
        • Wang S.
        • Cheng Z.
        • et al.
        Polydatin ameliorates diabetic cardiomyopathy via Sirt3 activation.
        Biochem Biophys Res Commun. 2017; 493: 1280-1287
        • Yu L.
        • Dong X.
        • Xue X.
        • et al.
        Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: role of SIRT6.
        J Pineal Res. 2021; 70e12698
        • Liu W.
        • Ruiz-Velasco A.
        • Wang S.
        • et al.
        Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling.
        Nat Commun. 2017; 8: 494
        • Deng F.
        • Wang S.
        • Zhang L.
        • et al.
        Propofol through upregulating Caveolin-3 attenuates post-hypoxic mitochondrial damage and cell death in H9C2 cardiomyocytes during hyperglycemia.
        Cell Physiol Biochem. 2018; 44: 279-292
        • Tao L.
        • Huang X.
        • Xu M.
        • Yang L.
        • Hua F.
        MiR-144 protects the heart from hyperglycemia-induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis.
        FASEB J. 2020; 34: 2173-2197
        • Emelyanova L.
        • Bai X.
        • Yan Y.
        • et al.
        Biphasic effect of metformin on human cardiac energetics.
        Transl Res. 2021; 229: 5-23
        • Zhang L.
        • Tian J.
        • Diao S.
        • Zhang G.
        • Xiao M.
        • Chang D.
        GLP-1 receptor agonist liraglutide protects cardiomyocytes from IL-1β-induced metabolic disturbance and mitochondrial dysfunction.
        Chem Biol Interact. 2020; 332109252
        • Yurista S.R.
        • Silljé H.H.W.
        • Oberdorf-Maass S.U.
        • et al.
        Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction.
        Eur J Heart Fail. 2019; 21: 862-873
        • Eirin A.
        • Ebrahimi B.
        • Kwon S.H.
        • et al.
        Restoration of mitochondrial cardiolipin attenuates cardiac damage in swine renovascular hypertension.
        J Am Heart Assoc. 2016; 5e003118
        • Chang W.
        • Zhang M.
        • Chen L.
        • Hatch G.M.
        Berberine inhibits oxygen consumption rate independent of alteration in cardiolipin levels in H9c2 cells.
        Lipids. 2017; 52: 961-967
        • 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
        • Santos J.M.
        • Tewari S.
        • Benite-Ribeiro S.A.
        The effect of exercise on epigenetic modifications of PGC1: the impact on type 2 diabetes.
        Med Hypotheses. 2014; 82: 748-753
        • Sriwijitkamol A.
        • Coletta D.K.
        • Wajcberg E.
        • et al.
        Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes.
        Diabetes. 2007; 56: 836-848
        • Wang P.
        • Wang D.
        • Yang Y.
        • et al.
        Tom70 protects against diabetic cardiomyopathy through its antioxidant and antiapoptotic properties.
        Hypertens Res. 2020; 43: 1047-1056
        • Ponce J.M.
        • Coen G.
        • Spitler K.M.
        • et al.
        Stress-induced cyclin C translocation regulates cardiac mitochondrial dynamics.
        J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2020; 9e014366
        • Tao A.
        • Xu X.
        • Kvietys P.
        • Kao R.
        • Martin C.
        • Rui T.
        Experimental diabetes mellitus exacerbates ischemia/reperfusion-induced myocardial injury by promoting mitochondrial fission: role of down-regulation of myocardial Sirt1 and subsequent Akt/Drp1 interaction.
        Int J Biochem Cell Biol. 2018; 105: 94-103
        • Apaijai N.
        • Charoenphandhu N.
        • Ittichaichareon J.
        • et al.
        Estrogen deprivation aggravates cardiac hypertrophy in nonobese Type 2 diabetic Goto-Kakizaki (GK) rats.
        BiosciRep. 2017; 37BSR20170886
        • Wang Y.
        • Gao P.
        • Wei C.
        • et al.
        Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway.
        Cell Death Dis. 2017; 8e2799
        • Parra V.
        • Verdejo H.E.
        • Iglewski M.
        • et al.
        Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 signaling pathway.
        Diabetes. 2014; 63: 75-88
        • Pennanen C.
        • Parra V.
        • López-Crisosto C.
        • et al.
        Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway.
        J Cell Sci. 2014; 127: 2659-2671
        • Mizuno M.
        • Kuno A.
        • Yano T.
        • et al.
        Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts.
        Physiol Rep. 2018; 6e13741
        • Wang J.
        • Chen P.
        • Cao Q.
        • Wang W.
        • Chang X.
        Traditional Chinese medicine Ginseng Dingzhi Decoction ameliorates myocardial fibrosis and high glucose-induced cardiomyocyte injury by regulating intestinal flora and mitochondrial dysfunction.
        Oxid Med Cell Longev. 2022; 20229205908
        • Qiao H.
        • Ren H.
        • Du H.
        • Zhang M.
        • Xiong X.
        • Lv R.
        Liraglutide repairs the infarcted heart: the role of the SIRT1/Parkin/mitophagy pathway.
        Mol Med Rep. 2018; 17: 3722-3734
        • Wang S.
        • Zhao Z.
        • Feng X.
        • et al.
        Melatonin activates parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition.
        J Cell Mol Med. 2018; 22: 5132-5144
        • Sun Y.
        • Lu F.
        • Yu X.
        • et al.
        Exogenous H2S promoted USP8 sulfhydration to regulate mitophagy in the hearts of db/db mice.
        Aging Dis. 2020; 11: 269-285
        • Belosludtseva N.V.
        • Starinets V.S.
        • Mikheeva I.B.
        • et al.
        Effect of the MPT pore inhibitor alisporivir on the development of mitochondrial dysfunction in the heart tissue of diabetic mice.
        Biology. 2021; 10: 839
        • Thai P.N.
        • Miller C.V.
        • King M.T.
        • et al.
        Ketone ester D-β-hydroxybutyrate-(R)-1,3 butanediol prevents decline in cardiac function in type 2 diabetic mice.
        J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2021; 10e020729