The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure

Abstract

This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions.

Keywords

Mitochondria / mitophagy / fibrosis / fibroblasts / remodeling / cardiac

References

[1] Shin D,Bohra C.Trends in the prevalence of metabolic syndrome and its components in the United States 2007-2014.Int J Cardiol2018;259:216-9

[2] Cornier MA,Hernandez TL.The metabolic syndrome.Endocr Rev2008;29:777-822

[3] Jia G,Sowers JR.Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity.Circ Res2018;122:624-38 PMCID:PMC5819359

[4] Lopaschuk GD.Metabolic abnormalities in the diabetic heart.Heart Fail Rev2002;7:149-59

[5] Boudina S,O’Neill BT,Young ME.Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity.Circulation2005;112:2686-95

[6] Boudina S,Theobald H.Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins.Diabetes2007;56:2457-66

[7] Peterson LR,Schechtman KB.Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women.Circulation2004;109:2191-6

[8] Peterson LR,McGill JB.Sex and type 2 diabetes: obesity-independent effects on left ventricular substrate metabolism and relaxation in humans.Obesity2012;20:802-10 PMCID:PMC3314727

[9] Giordano FJ.Oxygen, oxidative stress, hypoxia, and heart failure.J Clin Invest2005;115:500-8 PMCID:PMC1052012

[10] Birben E,Sackesen C,Kalayci O.Oxidative stress and antioxidant defense.World Allergy Organ J2012;5:9-19 PMCID:PMC3488923

[11] Andreyev AY,Starkov AA.Mitochondrial metabolism of reactive oxygen species.Biochemistry2005;70:200-14

[12] Dietl A.Targeting mitochondrial calcium handling and reactive oxygen species in heart failure.Curr Heart Fail Rep2017;14:338-49

[13] Bugger H,Jaishy B.Genetic loss of insulin receptors worsens cardiac efficiency in diabetes.J Mol Cell Cardiol2012;52:1019-26 PMCID:PMC3327790

[14] Qi Y,Zhu Q.Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance.Diabetes2013;62:3887-900 PMCID:PMC3806607

[15] Boudina S,Sena S.Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart.Circulation2009;119:1272-83 PMCID:PMC2739097

[16] Cai L,Wang G,Jiang Y.Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway.Diabetes2002;51:1938-48

[17] Shen E,Li Y.Rac1 is required for cardiomyocyte apoptosis during hyperglycemia.Diabetes2009;58:2386-95 PMCID:PMC2750234

[18] Santulli G,Reiken SR.Mitochondrial calcium overload is a key determinant in heart failure.Proc Natl Acad Sci USA2015;112:11389-94 PMCID:PMC4568687

[19] Flarsheim CE,Matlib MA.Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart.Am J Physiol1996;271:H192-202

[20] Tanaka Y,Kako KJ.Mitochondrial dysfunction observed in situ in cardiomyocytes of rats in experimental diabetes.Cardiovasc Res1992;26:409-14

[21] Stefani D, Raffaello A, Teardo E, Szabò I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.Nature2011;476:336-40 PMCID:PMC4141877

[22] Baughman JM,Girgis HS.Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter.Nature2011;476:341-5 PMCID:PMC3486726

[23] Kamer KJ.The molecular era of the mitochondrial calcium uniporter.Nat Rev Mol Cell Biol2015;16:545-53

[24] Kwong JQ.The mitochondrial calcium uniporter in the heart: energetics and beyond.J Physiol2017;595:3743-51 PMCID:PMC5471511

[25] Odagiri K,Kawashima H.Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes.J Mol Cell Cardiol2009;46:989-97

[26] Anderson EJ,Anderson CA,Chitwood WR.Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways.Am J Physiol Heart Circ Physiol2011;300:H118-24 PMCID:PMC3023249

[27] Honda HM,Weiss JN.Mitochondria and ischemia/reperfusion injury.Ann N Y Acad Sci2005;1047:248-58

[28] Riojas-Hernández A,Rodríguez-Mier D.Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes.Life Sci2015;141:32-43

[29] Diaz-Juarez J,Cividini F.Expression of the mitochondrial calcium uniporter in cardiac myocytes improves impaired mitochondrial calcium handling and metabolism in simulated hyperglycemia.Am J Physiol Cell Physiol2016;311:C1005-13 PMCID:PMC5206303

[30] Linton MF. The role of lipids and lipoproteins in atherosclerosis. In Endotext, Feingold, KR. editors. South Dartmouth, MA, 2000.

[31] White CR,Giordano S.High-density lipoprotein regulation of mitochondrial function. Adv Exp Med Biol 2017;982:407-29. PMCID:PMC5822681

[32] Huang Y,Riwanto M.Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex.J Clin Invest2013;123:3815-28 PMCID:PMC3754253

[33] Dadabayev AR,Latchoumycandane C,Lesnefsky EJ.Apolipoprotein A1 regulates coenzyme Q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction.J Nutr2014;144:1030-6 PMCID:PMC4056643

[34] Olkowicz M,Debski J.Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern.Metabolism2021;114:154400

[35] Oliveira HC,Alberici LC.Oxidative stress in atherosclerosis-prone mouse is due to low antioxidant capacity of mitochondria.FASEB J2005;19:278-80

[36] Knight-Lozano CA,Burow DL.Cigarette smoke exposure and hypercholesterolemia increase mitochondrial damage in cardiovascular tissues.Circulation2002;105:849-54

[37] Harmancey R,Taegtmeyer H.Adaptation and maladaptation of the heart in obesity.Hypertension2008;52:181-7 PMCID:PMC3660087

[38] Huffman KM,Hubal MJ.Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness.Diabetologia2014;57:2282-95 PMCID:PMC4182127

[39] Schrauwen P,Hesselink MK.An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix.FASEB J2001;15:2497-502

[40] Palomer X,Zarei M,Vázquez-Carrera M.PPARβ/δ and lipid metabolism in the heart.Biochim Biophys Acta2016;1861:1569-78

[41] Grossman W,McLaurin LP.Wall stress and patterns of hypertrophy in the human left ventricle.J Clin Invest1975;56:56-64 PMCID:PMC436555

[42] Bristow MR.Mechanisms of development of heart failure in the hypertensive patient.Cardiology1999;92:3-6; discussion 7

[43] Kupari M,Lommi J.Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure?.Eur Heart J2005;26:1790-6

[44] Carabello BA.Aortic stenosis: from pressure overload to heart failure.Heart Fail Clin2006;2:435-42

[45] Rimbaud S,Ventura-clapier R.Mitochondrial biogenesis in cardiac pathophysiology.Pharmacol Rep2009;61:131-8

[46] Molkentin JD.With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure.J Mol Cell Cardiol2009;46:130-6 PMCID:PMC2644412

[47] Doenst T,Schrepper A.Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload.Cardiovasc Res2010;86:461-70

[48] Bilsen M, van Nieuwenhoven FA, van der Vusse GJ. Metabolic remodelling of the failing heart: beneficial or detrimental?.Cardiovasc Res2009;81:420-8

[49] Wende AR.Lipotoxicity in the heart.Biochim Biophys Acta2010;1801:311-9 PMCID:PMC2823976

[50] Floras JS.Sympathetic nervous system activation in human heart failure: clinical implications of an updated model.J Am Coll Cardiol2009;54:375-85

[51] Opie LH.The adrenergic-fatty acid load in heart failure.J Am Coll Cardiol2009;54:1637-46

[52] Sharma S,Golfman L.Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart.FASEB J2004;18:1692-700

[53] Schrauwen P,Hoeks J.Mitochondrial dysfunction and lipotoxicity.Biochim Biophys Acta2010;1801:266-71

[54] Allard MF.Energy substrate metabolism in cardiac hypertrophy.Curr Hypertens Rep2004;6:430-5

[55] Jang JY,Liu J.The role of mitochondria in aging.J Clin Invest2018;128:3662-70 PMCID:PMC6118639

[56] Navarro A.The mitochondrial energy transduction system and the aging process.Am J Physiol Cell Physiol2007;292:C670-86

[57] Tatarková Z,Račay P.Effects of aging on activities of mitochondrial electron transport chain complexes and oxidative damage in rat heart.Physiol Res2011;60:281-9

[58] Dai DF,Chiao YA.Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart.Aging Cell2014;13:529-39

[59] Fraga CG,Park JW,Ames BN.Oxidative damage to DNA during aging: 8-hydroxy-2′-deoxyguanosine in rat organ DNA and urine.Proc Natl Acad Sci USA1990;87:4533-7 PMCID:PMC54150

[60] Pikó L,Bulpitt KJ.Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: evidence for an increased frequency of deletions/additions with aging.Mech Ageing Dev1988;43:279-93

[61] Kujoth GC,Pugh TD.Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.Science2005;309:481-4

[62] Nakada K,Chen CS.Correlation of functional and ultrastructural abnormalities of mitochondria in mouse heart carrying a pathogenic mutant mtDNA with a 4696-bp deletion.Biochem Biophys Res Commun2001;288:901-7

[63] Hom J.Morphological dynamics of mitochondria-a special emphasis on cardiac muscle cells.J Mol Cell Cardiol2009;46:811-20 PMCID:PMC2995918

[64] Dai DF.Cardiac aging in mice and humans: the role of mitochondrial oxidative stress.Trends Cardiovasc Med2009;19:213-20 PMCID:PMC2858758

[65] Tate EL.A morphometric study of the density of mitochondrial cristae in heart and liver of aging mice.J Gerontol1976;31:129-34

[66] Fleischer M,Backwinkel KP.[Ultrastructural morphometric analysis of normally loaded human myocardial left ventricles from young and old patients (author’s transl)].Virchows Arch A Pathol Anat Histol1978;380:123-33

[67] Lee HJ,Rapoport SI.Selective remodeling of cardiolipin fatty acids in the aged rat heart.Lipids Health Dis2006;5:2 PMCID:PMC1402292

[68] Tamburini I,Izzo R.Effects of dietary restriction on age-related changes in the phospholipid fatty acid composition of various rat tissues.Aging Clin Exp Res2004;16:425-31

[69] Schlame M.The role of cardiolipin in the structural organization of mitochondrial membranes.Biochim Biophys Acta2009;1788:2080-3 PMCID:PMC2757492

[70] Schlame M.Cardiolipin remodeling and the function of tafazzin.Biochim Biophys Acta2013;1831:582-8

[71] Khan A.Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system.Cardiovasc Res2002;54:25-35

[72] Johnson SC,Kaeberlein M.mTOR is a key modulator of ageing and age-related disease.Nature2013;493:338-45 PMCID:PMC3687363

[73] Kapahi P,Harper T,Sapin V.Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.Curr Biol2004;14:885-90 PMCID:PMC2754830

[74] Karamanlidis G,Garcia-Menendez L.Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure.Cell Metab2013;18:239-50 PMCID:PMC3779647

[75] Yang H,Shi Q.SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth.EMBO J2015;34:1110-25 PMCID:PMC4406655

[76] Lee CF,Garcia-Menendez L.Normalization of NAD+ redox balance as a therapy for heart failure.Circulation2016;134:883-94 PMCID:PMC5193133

[77] Zhang X,Liao X.MicroRNA-195 regulates metabolism in failing myocardium via alterations in sirtuin 3 expression and mitochondrial protein acetylation.Circulation2018;137:2052-67 PMCID:PMC6449058

[78] Cencioni C,Mai A.Sirtuin function in aging heart and vessels.J Mol Cell Cardiol2015;83:55-61

[79] Wang B,Sun YY.Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice.J Cell Mol Med2014;18:1599-611 PMCID:PMC4190906

[80] Sack MN.Mitochondrial metabolism, sirtuins, and aging.Cold Spring Harb Perspect Biol2012;4:a013102-a013102 PMCID:PMC3504438

[81] Walker MA.NAD(H) in mitochondrial energy transduction: implications for health and disease.Curr Opin Physiol2018;3:101-9 PMCID:PMC7112453

[82] Sundaresan NR,Pillai VB,Gupta MP.SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70.Mol Cell Biol2008;28:6384-401 PMCID:PMC2577434

[83] Sack MN.Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart.Am J Physiol Heart Circ Physiol2011;301:H2191-7 PMCID:PMC3233806

[84] Ghosh R,Symons JD.Protein and mitochondria quality control mechanisms and cardiac aging.Cells2020;9:933 PMCID:PMC7226975

[85] Muller S,Couppez M,Sommermeyer G.Specificity of antibodies raised against triacetylated histone H4.Mol Immunol1987;24:779-89

[86] Scarpulla RC.Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network.Biochim Biophys Acta2011;1813:1269-78 PMCID:PMC3035754

[87] Lehman JJ,Kovacs A,Medeiros DM.Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis.J Clin Invest2000;106:847-56 PMCID:PMC517815

[88] Russell LK,Lehman JJ.Cardiac-Specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-Dependent Manner.Circ Res2004;94:525-33

[89] Valori M,Tienari PJ.CD8+ cell somatic mutations in multiple sclerosis patients and controls-Enrichment of mutations in STAT3 and other genes implicated in hematological malignancies.PLoS One2021;16:e0261002 PMCID:PMC8651110

[90] Lelliott CJ,Petrovic N.Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance.PLoS Biol2006;4:e369 PMCID:PMC1634886

[91] Sonoda J,Chong LW,Evans RM.PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis.Proc Natl Acad Sci USA2007;104:5223-8 PMCID:PMC1829290

[92] Vianna CR,Coppari R.Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance.Cell Metab2006;4:453-64 PMCID:PMC1764615

[93] He X,Wang F.Peri-implantation lethality in mice lacking the PGC-1-related coactivator protein.Dev Dyn2012;241:975-83

[94] Gupte AA,Cordero-Reyes AM.Mechanical unloading promotes myocardial energy recovery in human heart failure.Circ Cardiovasc Genet2014;7:266-76 PMCID:PMC4394989

[95] Garnier A,Deloménie C,Veksler V.Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles.J Physiol2003;551:491-501 PMCID:PMC2343221

[96] Huss JM,Dufour CR.The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.Cell Metab2007;6:25-37

[97] Riehle C,Zaha VG.PGC-1β deficiency accelerates the transition to heart failure in pressure overload hypertrophy.Circ Res2011;109:783-93 PMCID:PMC3175248

[98] Hu X,Huang Y.Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload.Circ Res2008;103:1009-17 PMCID:PMC2877276

[99] Hu X,Lu Z.AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development.Hypertension2011;58:696-703 PMCID:PMC3182261

[100] Karamanlidis G,Couper GS,del Monte F.Defective DNA replication impairs mitochondrial biogenesis in human failing hearts.Circ Res2010;106:1541-8 PMCID:PMC2880225

[101] Scarpulla RC,Kelly DP.Transcriptional integration of mitochondrial biogenesis.Trends Endocrinol Metab2012;23:459-66 PMCID:PMC3580164

[102] Li H,Wilhelmsson H.Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy.Proc Natl Acad Sci USA2000;97:3467-72 PMCID:PMC16263

[103] Duncan JG,Medeiros DM,Kelly DP.Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway.Circulation2007;115:909-17 PMCID:PMC4322937

[104] Bugger H,Hu XX.Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3.Diabetes2008;57:2924-32 PMCID:PMC2570388

[105] Tao L,Xu M,Hua F.MiR-144 protects the heart from hyperglycemia-induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis.FASEB J2020;34:2173-97

[106] Chang LT,Wang CY.Downregulation of peroxisme proliferator activated receptor gamma co-activator 1alpha in diabetic rats.Int Heart J2006;47:901-10

[107] Chan DC.Dissecting mitochondrial fusion.Dev Cell2006;11:592-4

[108] Detmer SA.Functions and dysfunctions of mitochondrial dynamics.Nat Rev Mol Cell Biol2007;8:870-9

[109] Hoppins S.The molecular mechanism of mitochondrial fusion.Biochim Biophys Acta2009;1793:20-6

[110] Logan DC.Mitochondrial dynamics.New Phytol2003;160:463-78

[111] Griparic L,Orozco IJ,van der Bliek AM.Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria.J Biol Chem2004;279:18792-8

[112] Santel A.Control of mitochondrial morphology by a human mitofusin.J Cell Sci2001;114:867-74

[113] Lee YJ,Karbowski M,Youle RJ.Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis.Mol Biol Cell2004;15:5001-11 PMCID:PMC524759

[114] Pitts KR,Krueger EW.The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells.Mol Biol Cell1999;10:4403-17 PMCID:PMC25766

[115] Stojanovski D,Okamoto K.Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology.J Cell Sci2004;117:1201-10

[116] Gong G,Csordas G,Matkovich SJ.Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice.Science2015;350:aad2459 PMCID:PMC4747105

[117] Papanicolaou KN,Dabkowski ER.Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death.Am J Physiol Heart Circ Physiol2012;302:H167-79 PMCID:PMC3334239

[118] Chen Y,Dorn GW 2nd.Mitochondrial fusion is essential for organelle function and cardiac homeostasis.Circ Res2011;109:1327-31 PMCID:PMC3237902

[119] Papanicolaou KN,Ngoh GA.Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart.Circ Res2012;111:1012-26 PMCID:PMC3518037

[120] Ikeda Y,Maejima Y.Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress.Circ Res2015;116:264-78

[121] Kageyama Y,Seo K.Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain.EMBO J2014;33:2798-813 PMCID:PMC4282557

[122] Song M,Chen Y,Dorn GW 2nd.Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts.Cell Metab2015;21:273-86 PMCID:PMC4318753

[123] Song M,Fleischer JA,Dorn GW 2nd.Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence.Cell Metab2017;26:872-883.e5 PMCID:PMC5718956

[124] Wai T,Baker MJ.Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice.Science2015;350:aad0116

[125] Uchikado Y,Ohishi M.Current understanding of the pivotal role of mitochondrial dynamics in cardiovascular diseases and senescence.Front Cardiovasc Med2022;9:905072 PMCID:PMC9157625

[126] Bouche L,Tamareille S.DRP1 haploinsufficiency attenuates cardiac ischemia/reperfusion injuries.PLoS One2021;16:e0248554 PMCID:PMC7993837

[127] Brady NR,Gottlieb RA.Proapoptotic BCL-2 family members and mitochondrial dysfunction during ischemia/reperfusion injury, a study employing cardiac HL-1 cells and GFP biosensors.Biochim Biophys Acta2006;1757:667-78

[128] Le Page S,Fauconnier J.Increase in cardiac ischemia-reperfusion injuries in opa1+/- mouse model.PLoS One2016;11:e0164066 PMCID:PMC5056696

[129] Varanita T,Romanello V.The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage.Cell Metab2015;21:834-44 PMCID:PMC4457892

[130] Haileselassie B,Joshi AU.Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy.J Mol Cell Cardiol2019;130:160-9 PMCID:PMC6948926

[131] Hsiao YT,Wakasugi T.Cardiac mitofusin-1 is reduced in non-responding patients with idiopathic dilated cardiomyopathy.Sci Rep2021;11:6722 PMCID:PMC7990924

[132] Hu Q,Gutiérrez Cortés N.Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction.Circ Res2020;126:456-70 PMCID:PMC7035202

[133] Montaigne D,Coisne A.Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients.Circulation2014;130:554-64

[134] Tsushima K,Wende AR.Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission.Circ Res2018;122:58-73 PMCID:PMC5756120

[135] Wu QR,Liu PM.High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy.Cell Death Dis2021;12:216 PMCID:PMC7910592

[136] Chen L,Stice JP.Mitochondrial OPA1, apoptosis, and heart failure.Cardiovasc Res2009;84:91-9 PMCID:PMC2741347

[137] Guo Y,Qin X.Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart.Cardiovasc Res2018;114:979-91

[138] Shirakabe A,Ikeda Y.Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure.Circulation2016;133:1249-63

[139] Shou J.PINK1 phosphorylates Drp1(S616) to improve mitochondrial fission and inhibit the progression of hypertension-induced HFpEF.Int J Mol Sci2022;23:11934 PMCID:PMC9570161

[140] Thai PN,Miller C.Mitochondrial quality control in aging and heart failure: influence of ketone bodies and mitofusin-stabilizing peptides.Front Physiol2019;10:382 PMCID:PMC6467974

[141] Yu H,Mi L,Li L.Mitofusin 2 inhibits angiotensin II-induced myocardial hypertrophy.J Cardiovasc Pharmacol Ther2011;16:205-11

[142] Youle RJ.Mechanisms of mitophagy.Nat Rev Mol Cell Biol2011;12:9-14 PMCID:PMC4780047

[143] Quiles JM.Mitochondrial quality control and cellular proteostasis: two sides of the same coin.Front Physiol2020;11:515 PMCID:PMC7263099

[144] Gustafsson ÅB.Evolving and expanding the roles of mitophagy as a homeostatic and pathogenic process.Physiol Rev2019;99:853-92 PMCID:PMC6442924

[145] Onishi M,Sato M,Okamoto K.Molecular mechanisms and physiological functions of mitophagy.EMBO J2021;40:e104705 PMCID:PMC7849173

[146] Saito T,Sadoshima J.Molecular mechanisms and clinical implications of multiple forms of mitophagy in the heart.Cardiovasc Res2021;117:2730-41 PMCID:PMC8932294

[147] Billia F,Konecny F,Shen J.PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function.Proc Natl Acad Sci USA2011;108:9572-7 PMCID:PMC3111326

[148] Kubli DA,Gustafsson AB.Parkin deficiency results in accumulation of abnormal mitochondria in aging myocytes.Commun Integr Biol2013;6:e24511 PMCID:PMC3737749

[149] Song M,Burelle Y.Interdependence of parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts.Circ Res2015;117:346-51 PMCID:PMC4522211

[150] Kubli DA,Lee Y.Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction.J Biol Chem2013;288:915-26 PMCID:PMC3543040

[151] Wu S,Wang Q.Binding of FUN14 domain containing 1 with inositol 1,4,5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo.Circulation2017;136:2248-66 PMCID:PMC5716911

[152] Oka T,Yamaguchi O.Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.Nature2012;485:251-5 PMCID:PMC3378041

[153] Durga Devi T,Mäkinen P.Aggravated postinfarct heart failure in type 2 diabetes is associated with impaired mitophagy and exaggerated inflammasome activation.Am J Pathol2017;187:2659-73

[154] Chaanine AH,Stulak JM.Mitochondrial morphology, dynamics, and function in human pressure overload or ischemic heart disease with preserved or reduced ejection fraction.Circ Heart Fail2019;12:e005131

[155] Tong M,Zhai P.Alternative mitophagy protects the heart against obesity-associated cardiomyopathy.Circ Res2021;129:1105-21

[156] Boudina S.Diabetic cardiomyopathy revisited.Circulation2007;115:3213-23

[157] Aubert G,Horton JL.The failing heart relies on ketone bodies as a fuel.Circulation2016;133:698-705

[158] Ho KL,Connolly D.Metabolic, structural and biochemical changes in diabetes and the development of heart failure.Diabetologia2022;65:411-23

[159] Abel ED.Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy.Cardiovasc Res2011;90:234-42 PMCID:PMC3115280

[160] Boudina S.Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes.Physiology2006;21:250-8

[161] Bugger H.Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome.Clin Sci2008;114:195-210

[162] Bugger H.Mitochondria in the diabetic heart.Cardiovasc Res2010;88:229-40 PMCID:PMC2952534

[163] Rosca MG,Hoppel CL.Mitochondria in cardiac hypertrophy and heart failure.J Mol Cell Cardiol2013;55:31-41 PMCID:PMC3805050

[164] Goldberg IJ,Schulze PC.Lipid metabolism and toxicity in the heart.Cell Metab2012;15:805-12 PMCID:PMC3387529

[165] Cheng L,Qin Q.Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy.Nat Med2004;10:1245-50

[166] Chiu H,Blanton RM.Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy.Circ Res2005;96:225-33

[167] Chiu HC,Ford DA.A novel mouse model of lipotoxic cardiomyopathy.J Clin Invest2001;107:813-22 PMCID:PMC199569

[168] Finck BN,Leone TC.The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus.J Clin Invest2002;109:121-30 PMCID:PMC150824

[169] Haemmerle G,Zimmermann R.Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase.Science2006;312:734-7

[170] Schweiger M,Haemmerle G.Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism.J Biol Chem2006;281:40236-41

[171] Son NH,Yamashita H.Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice.J Clin Invest2007;117:2791-801 PMCID:PMC1964508

[172] Buchanan J,Hu P.Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity.Endocrinology2005;146:5341-9

[173] Christoffersen C,Lindegaard ML.Cardiac lipid accumulation associated with diastolic dysfunction in obese mice.Endocrinology2003;144:3483-90

[174] Borradaile NM,Harp JD,Ory DS.Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death.J Lipid Res2006;47:2726-37

[175] Sparagna GC,Buja LM.A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis.Am J Physiol Heart Circ Physiol2000;279:H2124-32

[176] Law BA,Moore KS.Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.FASEB J2018;32:1403-16 PMCID:PMC5892719

[177] He L,Long Q.Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity.Circulation2012;126:1705-16 PMCID:PMC3484985

[178] Haynie KR,Wicks SE,Mynatt RL.Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice.Diabetes Obes Metab2014;16:757-60 PMCID:PMC4057362

[179] Gélinas R,Bouchard B.Prolonged QT interval and lipid alterations beyond β-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts.Am J Physiol Heart Circ Physiol2011;301:H813-23 PMCID:PMC3191095

[180] Watanabe K,Takahashi T.Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity.J Biol Chem2000;275:22293-9

[181] Xiong D,James J.Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance.Am J Physiol Heart Circ Physiol2014;306:H326-38 PMCID:PMC3920141

[182] Basu R,Wang X.Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function.Am J Physiol Heart Circ Physiol2009;297:H2096-108

[183] Zhou YT,Karim A.Lipotoxic heart disease in obese rats: implications for human obesity.Proc Natl Acad Sci USA2000;97:1784-9 PMCID:PMC26513

[184] Beam J,Ye J.Excess linoleic acid increases collagen I/III ratio and “stiffens” the heart muscle following high fat diets.J Biol Chem2015;290:23371-84 PMCID:PMC4645600

[185] Inoguchi T,Handler E,Heath W.Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.Proc Natl Acad Sci USA1992;89:11059-63 PMCID:PMC50483

[186] Evcimen N, King GL. The role of protein kinase C activation and the vascular complications of diabetes.Pharmacol Res2007;55:498-510

[187] Sokolova M,Alfsnes K.Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts.Biochim Biophys Acta Mol Cell Biol Lipids2017;1862:234-45

[188] Ueno M,Zenimaru Y.Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice.Am J Physiol Endocrinol Metab2008;294:E1109-18

[189] Xiong Z,Zhao Z.Mst1 knockdown alleviates cardiac lipotoxicity and inhibits the development of diabetic cardiomyopathy in db/db mice.Biochim Biophys Acta Mol Basis Dis2020;1866:165806

[190] Torres CR.Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc.J Biol Chem1984;259:3308-17

[191] Ding F,Wang M,Xia Q.O-GlcNAcylation involvement in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2.Amino Acids2013;45:339-49

[192] Hu Y,Fricovsky E.Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose.J Biol Chem2009;284:547-55 PMCID:PMC2610513

[193] Lu S,Lu X.Hyperglycemia acutely increases cytosolic reactive oxygen species via O-linked GlcNAcylation and CaMKII activation in mouse ventricular myocytes.Circ Res2020;126:e80-96 PMCID:PMC7210078

[194] Ngoh GA,Facundo HT.Augmented O-GlcNAc signaling attenuates oxidative stress and calcium overload in cardiomyocytes.Amino Acids2011;40:895-911 PMCID:PMC3118675

[195] Palaniappan KK,Smith TJ.A chemical glycoproteomics platform reveals O-GlcNAcylation of mitochondrial voltage-dependent anion channel 2.Cell Rep2013;5:546-52 PMCID:PMC3869705

[196] Chatham JC,Wende AR.Role of O-linked N-acetylglucosamine protein modification in cellular (patho)physiology.Physiol Rev2021;101:427-93 PMCID:PMC8428922

[197] Gawlowski T,Scott B.Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes.J Biol Chem2012;287:30024-34 PMCID:PMC3436129

[198] Ahmed N.Advanced glycation endproducts-role in pathology of diabetic complications.Diabetes Res Clin Pract2005;67:3-21

[199] Singh R,Mori T.Advanced glycation end-products: a review.Diabetologia2001;44:129-46

[200] Vlassara H.Diabetes and advanced glycation endproducts.J Intern Med2002;251:87-101

[201] Barlovic DP,Jandeleit-Dahm KA.RAGE biology, atherosclerosis and diabetes.Clin Sci2011;121:43-55

[202] Hartog JW,Bakker SJ,van Veldhuisen DJ.Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications.Eur J Heart Fail2007;9:1146-55

[203] Nelson MB,Winden DR,Bikman BT.Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner.Am J Physiol Heart Circ Physiol2015;309:H63-9

[204] Yang YC,Chen CL.Pkcδ activation is involved in ROS-mediated mitochondrial dysfunction and apoptosis in cardiomyocytes exposed to advanced glycation end products (ages).Aging Dis2018;9:647-63 PMCID:PMC6065295

[205] Zhang M,Anilkumar N.Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: involvement of Nox2 (gp91phox)-containing NADPH oxidase.Circulation2006;113:1235-43

[206] Manigrasso MB,Ramasamy R.Unlocking the biology of RAGE in diabetic microvascular complications.Trends Endocrinol Metab2014;25:15-22 PMCID:PMC3877224

[207] Yu Y,Delguste F.Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway.Free Radic Biol Med2017;112:397-410

[208] Neviere R,Wang L,Boulanger E.Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions.Glycoconj J2016;33:607-17

[209] González A,Díez J.Myocardial interstitial fibrosis in heart failure: biological and translational perspectives.J Am Coll Cardiol2018;71:1696-706

[210] Kasner M,Lopez B.Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction.J Am Coll Cardiol2011;57:977-85

[211] Zile MR,Ikonomidis JS.Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.Circulation2015;131:1247-59

[212] González A,Ravassa S,Díez J.The complex dynamics of myocardial interstitial fibrosis in heart failure. Focus on collagen cross-linking.Biochim Biophys Acta Mol Cell Res2019;1866:1421-32

[213] López B,González A,Díez J.Collagen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure: potential role of lysyl oxidase.Hypertension2012;60:677-83

[214] Frangogiannis NG.Cardiac fibrosis.Cardiovasc Res2021;117:1450-88 PMCID:PMC8152700

[215] Sampson N,Zenzmaier C.Redox signaling as a therapeutic target to inhibit myofibroblast activation in degenerative fibrotic disease.Biomed Res Int2014;2014:131737 PMCID:PMC3950649

[216] Grosche J,Eble JA.More than a syllable in fib-ROS-is: the role of ROS on the fibrotic extracellular matrix and on cellular contacts.Mol Aspects Med2018;63:30-46

[217] Marinho HS,Cyrne L,Antunes F.Hydrogen peroxide sensing, signaling and regulation of transcription factors.Redox Biol2014;2:535-62 PMCID:PMC3953959

[218] Brodsky B.Molecular structure of the collagen triple helix.Adv Protein Chem2005;70:301-39

[219] Perret S,Bernocco S.Unhydroxylated triple helical collagen I produced in transgenic plants provides new clues on the role of hydroxyproline in collagen folding and fibril formation.J Biol Chem2001;276:43693-8

[220] Wagner K,Turnay J.Coexpression of α and β subunits of prolyl 4-hydroxylase stabilizes the triple helix of recombinant human type X collagen.Biochem J2000;352:907-11

[221] Barth D,Frank S,Moroder L.The role of cystine knots in collagen folding and stability, part II. Conformational properties of (Pro-Hyp-Gly)n model trimers with N- and C-terminal collagen type III cystine knots.Chemistry2003;9:3703-14

[222] Singh P,Schwarzbauer JE.Assembly of fibronectin extracellular matrix.Annu Rev Cell Dev Biol2010;26:397-419 PMCID:PMC3628685

[223] Goh KY,Song J.Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice.Redox Biol2019;21:101100 PMCID:PMC6330374

[224] Liu RM.Reciprocal regulation of TGF-β and reactive oxygen species: a perverse cycle for fibrosis.Redox Biol2015;6:565-77 PMCID:PMC4625010

[225] Barnes JL.Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases.Kidney Int2011;79:944-56 PMCID:PMC3675765

[226] Cucoranu I,Dikalova A.NAD(P)H oxidase 4 mediates transforming growth factor-β1-induced differentiation of cardiac fibroblasts into myofibroblasts.Circ Res2005;97:900-7

[227] Barcellos-Hoff MH.Redox-mediated activation of latent transforming growth factor-beta 1.Mol Endocrinol1996;10:1077-83

[228] Siwik DA,Colucci WS.Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts.Am J Physiol Cell Physiol2001;280:C53-60

[229] Sabri A,Lucchesi PA.Regulation of hypertrophic and apoptotic signaling pathways by reactive oxygen species in cardiac myocytes.Antioxid Redox Signal2003;5:731-40

[230] Takimoto E.Role of oxidative stress in cardiac hypertrophy and remodeling.Hypertension2007;49:241-8

[231] Aikawa R,Tanaka M.Reactive oxygen species in mechanical stress-induced cardiac hypertrophy.Biochem Biophys Res Commun2001;289:901-7

[232] Sabri A,Samarel AM,Lucchesi PA.Hydrogen peroxide activates mitogen-activated protein kinases and Na⁺-H⁺ exchange in neonatal rat cardiac myocytes.Cir Res1998;82:1053-62

[233] Wei S,Fliegel L,Lucchesi PA.Differential MAP kinase activation and Na⁺/H⁺ exchanger phosphorylation by H₂O₂ in rat cardiac myocytes.Am J Physiol Cell Physiol2001;281:C1542-50

[234] Tu VC,Chen QM.Signals of oxidant-induced cardiomyocyte hypertrophy: key activation of p70 S6 kinase-1 and phosphoinositide 3-kinase.J Pharmacol Exp Ther2002;300:1101-10

[235] Kwon S.H2O2 regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways.J Mol Cell Cardiol2003;35:615-21

[236] Amin JK,Pimental DR.Reactive oxygen species mediate alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes.J Mol Cell Cardiol2001;33:131-9

[237] Tanaka K,Takabatake T.Redox regulation of MAPK pathways and cardiac hypertrophy in adult rat cardiac myocyte.J Am Coll Cardiol2001;37:676-85

[238] Kuster GM,Adachi T.α-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes is mediated via thioredoxin-1-sensitive oxidative modification of thiols on ras.Circulation2005;111:1192-8

[239] Nah J,Mukai R.Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.Cardiovasc Res2022;118:2638-51

[240] Chen H,Clish C.Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy.J Cell Biol2015;211:795-805 PMCID:PMC4657172

[241] Danial NN.Cell death: critical control points.Cell2004;116:205-19

[242] Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental mechanisms of regulated cell death and implications for heart disease.Physiol Rev2019;99:1765-817 PMCID:PMC6890986

[243] Nakagawa T,Watanabe T.Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death.Nature2005;434:652-8

[244] Baines CP,Purcell NH.Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.Nature2005;434:658-62

[245] Karch J.Identifying the components of the elusive mitochondrial permeability transition pore.Proc Natl Acad Sci USA2014;111:10396-7 PMCID:PMC4115577

[246] Alavian KN,Lazrove E.An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore.Proc Natl Acad Sci USA2014;111:10580-5

[247] Carroll J,Ding S,Walker JE.Persistence of the permeability transition pore in human mitochondria devoid of an assembled ATP synthase.Proc Natl Acad Sci USA2019;116:12816-21 PMCID:PMC6601249

[248] He J,Carroll J,Fearnley IM.Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase.Proc Natl Acad Sci USA2017;114:3409-14 PMCID:PMC5380099

[249] Chipuk JE,Llambi F,Green DR.The BCL-2 family reunion.Mol Cell2010;37:299-310 PMCID:PMC3222298

[250] Gao XM,Dart AM.Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions.Pharmacol Ther2012;134:156-79

[251] Wende AR,Bugger H.Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.Mol Cell Biol2015;35:831-46 PMCID:PMC4323486

[252] Gao S,Shao Y.FABP5 deficiency impairs mitochondrial function and aggravates pathological cardiac remodeling and dysfunction.Cardiovasc Toxicol2021;21:619-29

[253] Yang D,Liu FY.Mitochondria in pathological cardiac hypertrophy research and therapy.Front Cardiovasc Med2021;8:822969 PMCID:PMC8804293

[254] Manning BD.AKT/PKB signaling: navigating the network.Cell2017;169:381-405 PMCID:PMC5546324

[255] O’Neill BT.Akt1 in the cardiovascular system: friend or foe?.J Clin Invest2005;115:2059-64 PMCID:PMC1180557

[256] Shiojima I,Izumiya Y.Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure.J Clin Invest2005;115:2108-18 PMCID:PMC1180541

[257] Zhu Y,O’Neill BT.Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation.Mol Endocrinol2013;27:172-84 PMCID:PMC3545208

[258] Akki A,Seymour AM.Compensated cardiac hypertrophy is characterised by a decline in palmitate oxidation.Mol Cell Biochem2008;311:215-24

[259] Fujii N,Igawa A.Saturated glucose uptake capacity and impaired fatty acid oxidation in hypertensive hearts before development of heart failure.Am J Physiol Heart Circ Physiol2004;287:H760-6

[260] Osorio JC,Linke A.Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-α in pacing-induced heart failure.Circulation2002;106:606-12

[261] Sambandam N,Brownsey RW.Energy metabolism in the hypertrophied heart.Heart Fail Rev2002;7:161-73

[262] Lydell C.Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts.Cardiovascr Res2002;53:841-51 PMCID:PMC2131743

[263] Summers MD.Comparative studies of baculovirus granulins and polyhedrins.Intervirology1976;6:168-80

[264] Sorokina N,McKinney RD.Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts.Circulation2007;115:2033-41

[265] Friehs I.Increased susceptibility of hypertrophied hearts to ischemic injury.Ann Thorac Surg2003;75:S678-84

[266] Sabbah HN,Lesch M.Progression of heart failure: a role for interstitial fibrosis.Mol Cell Biochem1995;147:29-34

[267] Boer RA,Van Veldhuisen DJ.The imbalance between oxygen demand and supply as a potential mechanism in the pathophysiology of heart failure: the role of microvascular growth and abnormalities.Microcirculation2003;10:113-26

[268] Semenza GL.Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1.Biochem J2007;405:1-9

[269] Webster KA,Hardeman E,Kedes L.Coordinate reciprocal trends in glycolytic and mitochondrial transcript accumulations during the in vitro differentiation of human myoblasts.J Cell Physiol1990;142:566-73

[270] Osterholt M,Schwarzer M.Alterations in mitochondrial function in cardiac hypertrophy and heart failure.Heart Fail Rev2013;18:645-56

[271] Bertoni AG,Massing MW,Burke GL.Heart failure prevalence, incidence, and mortality in the elderly with diabetes.Diabetes Care2004;27:699-703

[272] Rubler S,Yuceoglu YZ,Branwood AW.New type of cardiomyopathy associated with diabetic glomerulosclerosis.Am J Cardiol1972;30:595-602

[273] Dauriz M,Bonapace S.Prognostic impact of diabetes on long-term survival outcomes in patients with heart failure: a meta-analysis.Diabetes Care2017;40:1597-605

[274] Lind M,Olsson M,Svensson A.Glycaemic control and incidence of heart failure in 20 985 patients with type 1 diabetes: an observational study.Lancet2011;378:140-6

[275] Adeghate E.Structural changes in the myocardium during diabetes-induced cardiomyopathy.Heart Fail Rev2014;19:15-23

[276] Fang ZY,Marwick TH.Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications.Endocr Rev2004;25:543-67

[277] Jia G,Sowers JR.Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.Nat Rev Endocrinol2016;12:144-53 PMCID:PMC4753054

[278] Ramírez E,González-Bris A.Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking.Cardiovasc Diabetol2018;17:12 PMCID:PMC5765634

[279] Mytas DZ,Zairis MN,Pyrgakis VN.Diabetic myocardial disease: pathophysiology, early diagnosis and therapeutic options.J Diabetes Complications2009;23:273-82

[280] Wang J,Wang Q,Epstein PN.Causes and characteristics of diabetic cardiomyopathy.Rev Diabet Stud2006;3:108-17 PMCID:PMC1783586

[281] Baris OR,Neuhaus JF.Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging.Cell Metab2015;21:667-77

[282] Zhang Y,Hu N.Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function.Free Radic Biol Med2014;71:208-20 PMCID:PMC4068748

[283] HARMAN D.Aging: a theory based on free radical and radiation chemistry.J Gerontol1956;11:298-300

[284] Dutta D,Bernabei R,Marzetti E.Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities.Circ Res2012;110:1125-38 PMCID:PMC3353545

[285] Dai DF,Vermulst M.Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging.Circulation2009;119:2789-97 PMCID:PMC2858759

[286] Shi R,Kirshenbaum LA.Mitochondrial quality control: the role of mitophagy in aging.Trends Cardiovasc Med2018;28:246-60

[287] Benjamin EJ,Chiuve SE.Heart disease and stroke statistics-2017 update: a report from the american heart association.Circulation2017;135:e146-603

[288] Borlaug BA.Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum.Circulation2011;123:2006-13; discussion 2014 PMCID:PMC3420141

[289] Paulus WJ.A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.J Am Coll Cardiol2013;62:263-71

[290] Dunlay SM,Redfield MM.Epidemiology of heart failure with preserved ejection fraction.Nat Rev Cardiol2017;14:591-602

[291] McMurray JJ.Clinical practice. Systolic heart failure.N Engl J Med2010;362:228-38

[292] Redfield MM.Heart failure with preserved ejection fraction.N Engl J Med2016;375:1868-77

[293] Shah SJ,Borlaug BA.Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap.Circulation2016;134:73-90 PMCID:PMC4930115

[294] Zile MR,Hetzel SJ.Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction.Circulation2011;124:2491-501

[295] Borbély A,Papp Z.Cardiomyocyte stiffness in diastolic heart failure.Circulation2005;111:774-81

[296] van Heerebeek L,Niessen HW.Myocardial structure and function differ in systolic and diastolic heart failure.Circulation2006;113:1966-73

[297] van Heerebeek L,Falcão-Pires I.Low myocardial protein kinase G activity in heart failure with preserved ejection fraction.Circulation2012;126:830-9

[298] Westermann D,Kasner M.Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction.Circ Heart Fail2011;4:44-52

[299] Kumar AA,Chirinos JA.Mitochondrial dysfunction in heart failure with preserved ejection fraction.Circulation2019;139:1435-50 PMCID:PMC6414077

[300] Chen X,Xiong W.p53-dependent mitochondrial compensation in heart failure with preserved ejection fraction.J Am Heart Assoc2022;11:e024582 PMCID:PMC9238719

[301] Dai DF,Szeto H.Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy.J Am Coll Cardiol2011;58:73-82 PMCID:PMC3742010

[302] Tong D,Jiang N.NAD(+) repletion reverses heart failure with preserved ejection fraction.Circ Res2021;128:1629-41 PMCID:PMC8159891

[303] Zhang L,Ussher JR.Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy.Circ Heart Fail2013;6:1039-48

[304] Chaanine AH,Bergen RH 3rd.Mitochondrial integrity and function in the progression of early pressure overload-induced left ventricular remodeling.J Am Heart Assoc2017;6 PMCID:PMC5669187

[305] Bayeva M,Ardehali H.Mitochondria as a therapeutic target in heart failure.J Am Coll Cardiol2013;61:599-610 PMCID:PMC3594689

[306] Nakamura T.Current trends and future perspectives for heart failure treatment leveraging cGMP modifiers and the practical effector PKG.J Cardiol2021;78:261-8

[307] Jäger S,St-Pierre J.AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.Proc Natl Acad Sci USA2007;104:12017-22 PMCID:PMC1924552

[308] Kukidome D,Sonoda K.Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells.Diabetes2006;55:120-7

[309] Marin TL,Zhang F.AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1.Sci Signal2017;10 PMCID:PMC5830108

[310] Feng X,Ma L.Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.J Cell Mol Med2011;15:1572-81 PMCID:PMC3823201

[311] Gundewar S,Jha S.Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure.Circ Res2009;104:403-11 PMCID:PMC2709761

[312] Zou MH.Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK.Autophagy2013;9:624-5 PMCID:PMC3627682

[313] Magyar K,Palfi A.Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease.Clin Hemorheol Microcirc2012;50:179-87

[314] Rimbaud S,Piquereau J.Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure.PLoS One2011;6:e26391 PMCID:PMC3196575

[315] Takahashi S.Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells.Br J Nutr2012;107:774-80

[316] Thandapilly SJ,Behbahani J.Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure.Am J Hypertens2010;23:192-6

[317] Kim J,Kim Y,Ha J.AMPK activators: mechanisms of action and physiological activities.Exp Mol Med2016;48:e224 PMCID:PMC4855276

[318] Gollob MH,Tang AS.Identification of a gene responsible for familial Wolff-Parkinson-White syndrome.N Engl J Med2001;344:1823-31

[319] Blair E,Ashrafian H.Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.Hum Mol Genet2001;10:1215-20

[320] Arad M,Perez-Atayde AR.Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy.J Clin Invest2002;109:357-62 PMCID:PMC150860

[321] Milan D,Looft C.A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle.Science2000;288:1248-51

[322] Myers RW,Ehrhart J.Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy.Science2017;357:507-11

[323] Johnson WB,Able S,Harding SE.Profiling of cAMP and cGMP phosphodiesterases in isolated ventricular cardiomyocytes from human hearts: comparison with rat and guinea pig.Life Sci2012;90:328-36

[324] Takimoto E.Cyclic GMP-dependent signaling in cardiac myocytes.Circ J2012;76:1819-25

[325] Costa AD,West IC.Protein Kinase G Transmits the Cardioprotective Signal From Cytosol to Mitochondria.Circ Res2005;97:329-36

[326] Miyashita K,Tsujimoto H.Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity.Diabetes2009;58:2880-92 PMCID:PMC2780866

[327] Murad F.Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development.N Engl J Med2006;355:2003-11

[328] Armstrong PW,Anstrom KJ.Vericiguat in patients with heart failure and reduced ejection fraction.N Engl J Med2020;382:1883-93

[329] Pieske B,Lam CSP.Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study.Eur Heart J2017;38:1119-27 PMCID:PMC5400074

[330] Kansakar S,Verma D.Soluble guanylate cyclase stimulators in heart failure.Cureus2021;13:e17781

[331] Fiedler B,Smolenski A.Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes.Proc Natl Acad Sci USA2002;99:11363-8 PMCID:PMC123262

[332] Marchioli R,Macchia A.Vitamin E increases the risk of developing heart failure after myocardial infarction: results from the GISSI-Prevenzione trial.J Cardiovasc Med2006;7:347-50

[333] Smith RA,Gane AM.Delivery of bioactive molecules to mitochondria in vivo.Proc Natl Acad Sci USA2003;100:5407-12 PMCID:PMC154358

[334] Murphy MP.Targeting antioxidants to mitochondria by conjugation to lipophilic cations.Annu Rev Pharmacol Toxicol2007;47:629-56

[335] Junior RF, Dabkowski ER, Shekar KC, O Connell KA, Hecker PA, Murphy MP. MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload.Free Radic Biol Med2018;117:18-29 PMCID:PMC5866124

[336] Shi J,Hale SL.Bendavia restores mitochondrial energy metabolism gene expression and suppresses cardiac fibrosis in the border zone of the infarcted heart.Life Sci2015;141:170-8 PMCID:PMC4973309

[337] Siegel MP,Percival JM.Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice.Aging Cell2013;12:763-71 PMCID:PMC3772966

[338] Sabbah HN,Kohli S,Hachem S.Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure.Circ Heart Fail2016;9:e002206 PMCID:PMC4743543

[339] Chatfield KC,Chau S.Elamipretide improves mitochondrial function in the failing human heart.JACC Basic Transl Sci2019;4:147-57 PMCID:PMC6488757

[340] Dey S,Sidor A,O’Rourke B.Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure.Circ Res2018;123:356-71 PMCID:PMC6057154

[341] Liang HL,Bosnjak Z.SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery.Free Radic Biol Med2010;49:1550-60 PMCID:PMC3863116

[342] Ni R,Xiong S.Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy.Free Radic Biol Med2016;90:12-23 PMCID:PMC5066872

[343] Rushworth GF.Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits.Pharmacol Ther2014;141:150-9

[344] Faghfouri AH,Tavakoli-Rouzbehani OM.The effects of N-acetylcysteine on inflammatory and oxidative stress biomarkers: A systematic review and meta-analysis of controlled clinical trials.Eur J Pharmacol2020;884:173368

[345] Liu C,Shen MZ.N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition.BMC Cardiovasc Disord2015;15:84 PMCID:PMC4525750

[346] Pajor AM.Cloning and functional expression of a mammalian Na+/nucleoside cotransporter. A member of the SGLT family.J Biol Chem1992;267:3557-60

[347] Diedrich DF.Competitive inhibition of intestinal glucose transport by phlorizin analogs.Arch Biochem Biophys1966;117:248-56

[348] Neal B,Mahaffey KW.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med2017;377:644-57

[349] Tanaka A.Exploration of the clinical benefits of sodium glucose co-transporter 2 inhibitors in diabetic patients with concomitant heart failure.Cardiovasc Diabetol2018;17:74 PMCID:PMC5968589

[350] Wiviott SD,Bonaca MP.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med2019;380:347-57

[351] Zinman B,Lachin JM.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med2015;373:2117-28

[352] Mizuno M,Yano T.Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts.Physiol Rep2018;6:e13741 PMCID:PMC6014462

[353] Zhou H,Zhu P,Chen Y.Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission.Redox Biol2018;15:335-46 PMCID:PMC5756062

[354] Ferrannini E,Mayoux E.CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis.Diabetes Care2016;39:1108-14

[355] Santos-Gallego CG,San Antonio R.Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics.J Am Coll Cardiol2019;73:1931-44

[356] Yurista SR,Oberdorf-Maass SU.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 Fail2019;21:862-73

[357] Ajoolabady A,Aghanejad A,Ren J.Mitophagy receptors and mediators: therapeutic targets in the management of cardiovascular ageing.Ageing Res Rev2020;62:101129

[358] Chen G,Kepp O.Mitophagy: an emerging role in aging and age-associated diseases.Front Cell Dev Biol2020;8:200 PMCID:PMC7113588

[359] Laker RC,Wilson RJ.Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy.Nat Commun2017;8:548 PMCID:PMC5601463

[360] Mariño G,Eisenberg T.Regulation of autophagy by cytosolic acetyl-coenzyme A.Mol Cell2014;53:710-25

[361] Eisenberg T,Schroeder S.Cardioprotection and lifespan extension by the natural polyamine spermidine.Nat Med2016;22:1428-38 PMCID:PMC5806691

[362] Yang M,Zhang Y.Mitophagy and mitochondrial integrity in cardiac ischemia-reperfusion injury.Biochim Biophys Acta Mol Basis Dis2019;1865:2293-302