Abstract
Mitochondria are dynamic organelles that alter their morphology through fission (fragmentation) and fusion (elongation). These morphological changes correlate highly with mitochondrial functional adaptations to stressors, such as hypoxia, pressure overload, and inflammation, and are important in the setting of heart failure. Pathological mitochondrial remodeling, characterized by increased fission and reduced fusion, is associated with impaired mitochondrial respiration, increased mitochondrial oxidative stress, abnormal cytoplasmic calcium handling, and increased cardiomyocyte apoptosis. Considering the impact of the mitochondrial morphology on mitochondrial behavior and cardiomyocyte performance, altered mitochondrial dynamics could be expected to induce or exacerbate the pathogenesis and progression of heart failure. However, whether alterations in mitochondrial fission and fusion accelerate or retard the progression of heart failure has been the subject of intense debate. In this review, we first describe the physiological processes and regulatory mechanisms of mitochondrial fission and fusion. Then, we extensively discuss the pathological contributions of mitochondrial fission and fusion to heart failure. Lastly, we examine potential therapeutic approaches targeting mitochondrial fission/fusion to treat patients with heart failure.
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References
Adaniya SM, O-Uchi J, Cypress MW, Kusakari Y, Jhun BS (2019) Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology. Am J Physiol Cell Physiol 316:C583-C604. https://doi.org/10.1152/ajpcell.00523.2018
Ahuja P, Wanagat J, Wang Z et al (2013) Divergent mitochondrial biogenesis responses in human cardiomyopathy. Circulation 127:1957–1967. https://doi.org/10.1161/circulationaha.112.001219
Aoki H, Kang P M, Hampe J et al (2002) Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes. J Biol Chem 277:10244–10250. https://doi.org/10.1074/jbc.M112355200
Bao D, Zhao J, Zhou X et al (2019) Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene 38:5007–5020. https://doi.org/10.1038/s41388-019-0772-z
Cereghetti GM, Stangherlin A, Martins de Brito O et al (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci USA 105:15803–15808. https://doi.org/10.1073/pnas.0808249105
Chaanine AH, Gordon RE, Kohlbrenner E et al (2013) Potential role of BNIP3 in cardiac remodeling, myocardial stiffness, and endoplasmic reticulum: mitochondrial calcium homeostasis in diastolic and systolic heart failure. Circ Heart Fail 6:572–583. https://doi.org/10.1161/circheartfailure.112.000200
Chaanine AH, Jeong D, Liang L et al (2012) JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 3:265. https://doi.org/10.1038/cddis.2012.5
Chaanine AH, Joyce LD, Stulak JM et al (2019a) Mitochondrial morphology, dynamics, and function in human pressure overload or ischemic heart disease with preserved or reduced ejection fraction. Circ Heart Fail 12:e005131. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005131
Chaanine AH, Joyce LD, Stulak JM et al (2019b) Mitochondrial morphology, dynamics, and function in human pressure overload or ischemic heart disease with preserved or reduced ejection fraction. Circ Heart Fail 12:e005131. https://doi.org/10.1161/circheartfailure.118.005131
Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann NY Acad Sci 1201:34–39. https://doi.org/10.1111/j.1749-6632.2010.05629.x
Chang X, Li Y, Cai C et al (2022a) Mitochondrial quality control mechanisms as molecular targets in diabetic heart. Metabolism 137:155313. https://doi.org/10.1016/j.metabol.2022.155313
Chang X, Lochner A, Wang HH et al (2021) Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control. Theranostics 11:6766–6785. https://doi.org/10.7150/thno.60143
Chang X, Toan S, Li R, Zhou H (2022b) Therapeutic strategies in ischemic cardiomyopathy: focus on mitochondrial quality surveillance. EBioMedicine 84:104260. https://doi.org/10.1016/j.ebiom.2022.104260
Chang YW, Chang YT, Wang Q et al (2013) Quantitative phosphoproteomic study of pressure-overloaded mouse heart reveals dynamin-related protein 1 as a modulator of cardiac hypertrophy. Mol Cell Proteomics 12:3094–3107. https://doi.org/10.1074/mcp.M113.027649
Chen L, Gong Q, Stice J P, and Knowlton AA (2009) Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 84:91–99. https://doi.org/10.1093/cvr/cvp181
Chen L, Liu B, Qin Y et al (2021) Mitochondrial fusion protein Mfn2 and its role in heart failure. Front Mol Biosci 8:681237. https://doi.org/10.3389/fmolb.2021.681237
Chen L, Liu T, Tran A et al (2012) OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. J Am Heart Assoc 1:e003012. https://doi.org/10.1161/jaha.112.003012
Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475. https://doi.org/10.1126/science.1231031
Cho DH, Nakamura T, Fang J et al (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105. https://doi.org/10.1126/science.1171091
Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101:15927–15932. https://doi.org/10.1073/pnas.0407043101
Civiletto G, Varanita T, Cerutti R et al (2015) Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models. Cell Metab 21:845–854. https://doi.org/10.1016/j.cmet.2015.04.016
Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8:939–944. https://doi.org/10.1038/sj.embor.7401062
Di Nottia M, Verrigni D, Torraco A et al (2021) Mitochondrial dynamics: molecular mechanisms, related primary mitochondrial disorders and therapeutic approaches. Genes (Basel) 12. https://doi.org/10.3390/genes12020247
Donnarumma E, Kohlhaas M, Vimont E et al (2022) Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure. Nat Commun 13:6634. https://doi.org/10.1038/s41467-022-34316-3
Dorn GW 2nd (2015) Mitochondrial dynamism and heart disease: changing shape and shaping change. EMBO Mol Med 7:865–877. https://doi.org/10.15252/emmm.201404575
Dorn GW 2nd (2020) Mitofusins as mitochondrial anchors and tethers. J Mol Cell Cardiol 142:146–153. https://doi.org/10.1016/j.yjmcc.2020.04.016
Dorn GW 2nd, Clark CF, Eschenbacher WH et al (2011) MARF and Opa1 control mitochondrial and cardiac function in Drosophila. Circ Res 108:12–17. https://doi.org/10.1161/circresaha.110.236745
Eisner V, Cupo RR, Gao E et al (2017) Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. Proc Natl Acad Sci USA 114:E859-e868. https://doi.org/10.1073/pnas.1617288114
Fang L, Moore XL, Gao XM et al (2007) Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci 80:2154–2160. https://doi.org/10.1016/j.lfs.2007.04.003
Ferreira JCB, Campos JC, Qvit N et al (2019) A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats. Nat Commun 10:329. https://doi.org/10.1038/s41467-018-08276-6
Gao D, Zhang L, Dhillon R et al (2013) Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart. PLoS One 8:e60967. https://doi.org/10.1371/journal.pone.0060967
Gao S, Hu J (2021) Mitochondrial fusion: the machineries in and out. Trends Cell Biol 31:62–74. https://doi.org/10.1016/j.tcb.2020.09.008
Gawlowski T, Suarez J, Scott B et al (2012) Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-beta-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem 287:30024–30034. https://doi.org/10.1074/jbc.M112.390682
Gilkerson R, De La Torre P, St Vallier S (2021) Mitochondrial OMA1 and OPA1 as gatekeepers of organellar structure/function and cellular stress response. Front Cell Dev Biol 9:626117. https://doi.org/10.3389/fcell.2021.626117
Glauser L, Sonnay S, Stafa K, Moore DJ (2011) Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem 118:636–645. https://doi.org/10.1111/j.1471-4159.2011.07318.x
Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598. https://doi.org/10.1038/ncb2220
Gong G, Song M, Csordas G et al (2015) Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350:aad2459. https://doi.org/10.1126/science.aad2459
Guo C, Hildick KL, Luo J et al (2013) SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. EMBO J 32:1514–1528. https://doi.org/10.1038/emboj.2013.65
Hall AR, Burke N, Dongworth RK, Hausenloy DJ (2014) Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. Br J Pharmacol 171:1890–1906. https://doi.org/10.1111/bph.12516
Hall AR, Burke N, Dongworth RK, et al (2016) Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell Death Dis 7:e2238. https://doi.org/10.1038/cddis.2016.139
Han XJ, Lu YF, Li SA et al (2008) CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182:573–585. https://doi.org/10.1083/jcb.200802164
Hom J, Yu T, Yoon Y, Porter G, Sheu SS (2010) Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes. Biochim Biophys Acta 1797:913–921. https://doi.org/10.1016/j.bbabio.2010.03.018
Horn SR, Thomenius MJ, Johnson ES et al (2011) Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability. Mol Biol Cell 22:1207–1216. https://doi.org/10.1091/mbc.E10-07-0567
Hu C, Huang Y, Li L (2017) Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals. Int J Mol Sci 18. https://doi.org/10.3390/ijms18010144
Hu J, Liu T, Fu F et al (2022) Omentin1 ameliorates myocardial ischemia-induced heart failure via SIRT3/FOXO3a-dependent mitochondrial dynamical homeostasis and mitophagy. J Transl Med 20:447. https://doi.org/10.1186/s12967-022-03642-x
Huang CY, Lai CH, Kuo CH et al (2018) Inhibition of ERK-Drp1 signaling and mitochondria fragmentation alleviates IGF-IIR-induced mitochondria dysfunction during heart failure. J Mol Cell Cardiol 122:58–68. https://doi.org/10.1016/j.yjmcc.2018.08.006
Ikeda Y, Shirakabe A, Maejima Y et al (2015) Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res 116:264–278. https://doi.org/10.1161/circresaha.116.303356
Jang S, Javadov S (2020) OPA1 regulates respiratory supercomplexes assembly: the role of mitochondrial swelling. Mitochondrion 51:30–39. https://doi.org/10.1016/j.mito.2019.11.006
Jiang X, Jiang H, Shen Z, Wang X (2014) Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis. Proc Natl Acad Sci USA 111:14782–14787. https://doi.org/10.1073/pnas.1417253111
Jin Q, Li R, Hu N et al (2018) DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol 14:576–587. https://doi.org/10.1016/j.redox.2017.11.004
Kalia R, Wang RY-R, Yusuf A et al (2018) Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature 558:401–405. https://doi.org/10.1038/s41586-018-0211-2
Kalkhoran SB, Kriston-Vizi J, Hernandez-Resendiz S et al (2022) Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission. Cardiovasc Res 118:282–294. https://doi.org/10.1093/cvr/cvaa343
Kane LA, Youle RJ (2010) Mitochondrial fission and fusion and their roles in the heart. J Mol Med (Berl) 88:971–979. https://doi.org/10.1007/s00109-010-0674-6
Kasahara A, Cipolat S, Chen Y, Dorn GW, 2nd, and Scorrano L, (2013) Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling. Science 342:734–737. https://doi.org/10.1126/science.1241359
Kashatus DF, Lim KH, Brady DC et al (2011) RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol 13:1108–1115. https://doi.org/10.1038/ncb2310
Kashatus JA, Nascimento A, Myers LJ et al (2015) Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 57:537–551. https://doi.org/10.1016/j.molcel.2015.01.002
Kim DI, Lee KH, Gabr AA et al (2016) Abeta-induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochim Biophys Acta 1863:2820–2834. https://doi.org/10.1016/j.bbamcr.2016.09.003
Leboucher GP, Tsai YC, Yang M et al (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol Cell 47:547–557. https://doi.org/10.1016/j.molcel.2012.05.041
Lee JY, Kapur M, Li M et al (2014) MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria. J Cell Sci 127:4954–4963. https://doi.org/10.1242/jcs.157321
Li J, Dang X, Franco A, Dorn GW, 2nd, (2022) Reciprocal regulation of mitofusin 2-mediated mitophagy and mitochondrial fusion by different PINK1 phosphorylation events. Front Cell Dev Biol 10:868465. https://doi.org/10.3389/fcell.2022.868465
Liu J, Yan W, Zhao X et al (2019) Sirt3 attenuates post-infarction cardiac injury via inhibiting mitochondrial fission and normalization of AMPK-Drp1 pathways. Cell Signal 53:1–13. https://doi.org/10.1016/j.cellsig.2018.09.009
Liu T, Chen L, Kim E et al (2014) Mitochondrial proteome remodeling in ischemic heart failure. Life Sci 101:27–36. https://doi.org/10.1016/j.lfs.2014.02.004
Liu YJ, McIntyre RL, Janssens GE, Houtkooper RH (2020) Mitochondrial fission and fusion: a dynamic role in aging and potential target for age-related disease. Mech Ageing Dev 186:111212. https://doi.org/10.1016/j.mad.2020.111212
Ma L, Zou R, Shi W et al (2022) SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways. Theranostics 12:5034–5050. https://doi.org/10.7150/thno.75121
Makino A, Suarez J, Gawlowski T et al (2011) Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol 300:R1296-1302. https://doi.org/10.1152/ajpregu.00437.2010
Maneechote C, Palee S, Kerdphoo S et al (2019) Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury. Clin Sci (Lond) 133:497–513. https://doi.org/10.1042/CS20190014
Menezes TN, Ramalho LS, Bechara LRG, Ferreira JCB (2020) Targeting mitochondrial fission-fusion imbalance in heart failure. Curr Tissue Microenviron Rep 1:239–247. https://doi.org/10.1007/s43152-020-00023-8
Meyer JN, Leuthner TC, Luz AL (2017) Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology 391:42–53. https://doi.org/10.1016/j.tox.2017.07.019
Mondal NK, Behera J, Kelly KE et al (2019) Tetrahydrocurcumin epigenetically mitigates mitochondrial dysfunction in brain vasculature during ischemic stroke. Neurochem Int 122:120–138. https://doi.org/10.1016/j.neuint.2018.11.015
Nakamura M, Sadoshima J (2018) Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15:387–407. https://doi.org/10.1038/s41569-018-0007-y
Nan J, Zhu W, Rahman MS et al (2017) Molecular regulation of mitochondrial dynamics in cardiac disease. Biochim Biophys Acta Mol Cell Res 1864:1260–1273. https://doi.org/10.1016/j.bbamcr.2017.03.006
Nizami HL, Katare PB, Prabhakar P et al (2022) Paricalcitol attenuates metabolic syndrome-associated heart failure through enhanced mitochondrial fusion. Oxid Med Cell Longev 2022:5554290. https://doi.org/10.1155/2022/5554290
Noone J, O’Gorman DJ, Kenny HC (2022) OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle. Trends Endocrinol Metab 33:710–721. https://doi.org/10.1016/j.tem.2022.07.003
Oi M, Donner D, Peart J et al (2018) Pravastatin improves risk factors but not ischaemic tolerance in obese rats. Eur J Pharmacol 826:148–157. https://doi.org/10.1016/j.ejphar.2018.02.050
Ong SB, Kwek XY, Katwadi K et al (2019) Targeting mitochondrial fission using Mdivi-1 in a clinically relevant large animal model of acute myocardial infarction: a pilot study. Int J Mol Sci 20. https://doi.org/10.3390/ijms20163972
Ong SB, Subrayan S, Lim SY et al (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022. https://doi.org/10.1161/circulationaha.109.906610
Papanicolaou KN, Khairallah RJ, Ngoh GA et al (2011) Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 31:1309–1328. https://doi.org/10.1128/mcb.00911-10
Papanicolaou KN, Ngoh GA, Dabkowski ER et al (2012) 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 Physiol 302:H167-179. https://doi.org/10.1152/ajpheart.00833.2011
Park YY, Lee S, Karbowski M et al (2010) Loss of MARCH5 mitochondrial E3 ubiquitin ligase induces cellular senescence through dynamin-related protein 1 and mitofusin 1. J Cell Sci 123:619–626. https://doi.org/10.1242/jcs.061481
Park YY, Nguyen OT, Kang H, Cho H (2014) MARCH5-mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and cell survival. Cell Death Dis 5:e1172. https://doi.org/10.1038/cddis.2014.142
Pegadraju H, Abby Thomas J, Kumar R (2022) Mechanistic and therapeutic role of Drp1 in the pathogenesis of stroke. Gene 855:147130. https://doi.org/10.1016/j.gene.2022.147130
Pennanen C, Parra V, López-Crisosto C et al (2014) Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. J Cell Sci 127:2659–2671. https://doi.org/10.1242/jcs.139394
Pirzeh L, Babapour V, Badalzadeh R, Panahi N (2019) Pretreatment with vildagliptin boosts ischemic-postconditioning effects on cardioprotection and expression profile of genes regulating autophagy and mitochondrial fission/fusion in diabetic heart with reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 392:1371–1382. https://doi.org/10.1007/s00210-019-01660-z
Prudent J, Zunino R, Sugiura A et al (2015) MAPL SUMOylation of Drp1 stabilizes an ER/mitochondrial platform required for cell death. Mol Cell 59:941–955. https://doi.org/10.1016/j.molcel.2015.08.001
Pyakurel A, Savoia C, Hess D, Scorrano L (2015) Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell 58:244–254. https://doi.org/10.1016/j.molcel.2015.02.021
Qi X, Disatnik MH, Shen N, Sobel RA, Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell 22:256–265. https://doi.org/10.1091/mbc.E10-06-0551
Ranieri M, Brajkovic S, Riboldi G et al (2013) Mitochondrial fusion proteins and human diseases. Neurol Res Int 2013:293893. https://doi.org/10.1155/2013/293893
Ren L, Chen X, Chen X et al (2020) Mitochondrial dynamics: fission and fusion in fate determination of mesenchymal stem cells. Front Cell Dev Biol 8:580070. https://doi.org/10.3389/fcell.2020.580070
Riba A, Deres L, Eros K et al (2017) Doxycycline protects against ROS-induced mitochondrial fragmentation and ISO-induced heart failure. PLoS One 12:e0175195. https://doi.org/10.1371/journal.pone.0175195
Samant SA, Zhang HJ, Hong Z et al (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34:807–819. https://doi.org/10.1128/mcb.01483-13
Senyilmaz D, Virtue S, Xu X et al (2015) Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature 525:124–128. https://doi.org/10.1038/nature14601
Serasinghe MN, Wieder SY, Renault TT et al (2015) Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57:521–536. https://doi.org/10.1016/j.molcel.2015.01.003
Sharp WW, Fang YH, Han M et al (2014) Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission. Faseb j 28:316–326. https://doi.org/10.1096/fj.12-226225
Shou J, Huo Y (2022) PINK1 Phosphorylates Drp1(S616) to improve mitochondrial fission and inhibit the progression of hypertension-induced HFpEF. Int J Mol Sci 23. https://doi.org/10.3390/ijms231911934
So EC, Hsing CH, Liang CH, Wu SN (2012) The actions of mdivi-1, an inhibitor of mitochondrial fission, on rapidly activating delayed-rectifier K(+) current and membrane potential in HL-1 murine atrial cardiomyocytes. Eur J Pharmacol 683:1–9. https://doi.org/10.1016/j.ejphar.2012.02.012
Song M, Franco A, Fleischer JA, Zhang L, Dorn GW, 2nd, (2017) Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab 26:872-883.e875. https://doi.org/10.1016/j.cmet.2017.09.023
Song Z, Chen H, Fiket M, Alexander C, Chan DC (2007) OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 178:749–755. https://doi.org/10.1083/jcb.200704110
Sugiura A, Nagashima S, Tokuyama T et al (2013) MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol Cell 51:20–34. https://doi.org/10.1016/j.molcel.2013.04.023
Sui YB, Xiu J, Wei JX et al (2021) Shen Qi Li Xin formula improves chronic heart failure through balancing mitochondrial fission and fusion via upregulation of PGC-1α. J Physiol Sci 71:32. https://doi.org/10.1186/s12576-021-00816-y
Sumida M, Doi K, Ogasawara E et al (2015) Regulation of mitochondrial dynamics by dynamin-related protein-1 in acute cardiorenal syndrome. J Am Soc Nephrol 26:2378–2387. https://doi.org/10.1681/asn.2014080750
Sun D, Wang J, Toan S et al (2022) Molecular mechanisms of coronary microvascular endothelial dysfunction in diabetes mellitus: focus on mitochondrial quality surveillance. Angiogenesis 25:307–329. https://doi.org/10.1007/s10456-022-09835-8
Sun X, Yang Y, Xie Y et al (2018) Protective role of STVNa in myocardial ischemia reperfusion injury by inhibiting mitochondrial fission. Oncotarget 9:1898–1905. https://doi.org/10.18632/oncotarget.22969
Tanajak P, Sa-Nguanmoo P, Sivasinprasasn S et al (2018) Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J Endocrinol 236:69–84. https://doi.org/10.1530/JOE-17-0457
Toyama EQ, Herzig S, Courchet J et al (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351:275–281. https://doi.org/10.1126/science.aab4138
Varanita T, Soriano ME, Romanello V et al (2015) The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab 21:834–844. https://doi.org/10.1016/j.cmet.2015.05.007
Wai T, García-Prieto J, Baker MJ et al (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116. https://doi.org/10.1126/science.aad0116
Wang H, Song P, Du L et al (2011) Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem 286:11649–11658. https://doi.org/10.1074/jbc.M110.144238
Wang J, Zhu P, Toan S et al (2020) Pum2-Mff axis fine-tunes mitochondrial quality control in acute ischemic kidney injury. Cell Biol Toxicol 36:365–378. https://doi.org/10.1007/s10565-020-09513-9
Wang S, Zhu H, Li R et al (2022) DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury. Sci Signal 15:eabh1121. https://doi.org/10.1126/scisignal.abh1121
Wang W, Wang Y, Long J et al (2012) Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 15:186–200. https://doi.org/10.1016/j.cmet.2012.01.009
Wang Y, Jasper H, Toan S et al (2021) Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury. Redox Biol 45:102049. https://doi.org/10.1016/j.redox.2021.102049
Wang Y, Serricchio M, Jauregui M et al (2015) Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy 11:595–606. https://doi.org/10.1080/15548627.2015.1034408
Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884. https://doi.org/10.1038/nrm3013
Win S, Than TA, Fernandez-Checa JC, Kaplowitz N (2014) JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis 5:e989. https://doi.org/10.1038/cddis.2013.522
Xia Y, Chen Z, Chen A et al (2017) LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy. J Mol Cell Cardiol 108:138–148. https://doi.org/10.1016/j.yjmcc.2017.06.003
Xie Q, Wu Q, Horbinski CM et al (2015) Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci 18:501–510. https://doi.org/10.1038/nn.3960
Xin T, Lv W, Liu D, Jing Y, Hu F (2020) Opa1 reduces hypoxia-induced cardiomyocyte death by improving mitochondrial quality control. Front Cell Dev Biol 8:853. https://doi.org/10.3389/fcell.2020.00853
Xiong W, Ma Z, An D et al (2019) Mitofusin 2 participates in mitophagy and mitochondrial fusion against angiotensin II-induced cardiomyocyte injury. Front Physiol 10:411. https://doi.org/10.3389/fphys.2019.00411
Xu S, Wang P, Zhang H et al (2016) CaMKII induces permeability transition through Drp1 phosphorylation during chronic beta-AR stimulation. Nat Commun 7:13189. https://doi.org/10.1038/ncomms13189
Yang Y, Tian Y, Hu S et al (2017) Extract of Sheng-Mai-San ameliorates myocardial ischemia-induced heart failure by modulating Ca(2+)-calcineurin-mediated Drp1 signaling pathways. Int J Mol Sci 18. https://doi.org/10.3390/ijms18091825
Yeh CH, Chou YJ, Kao CH, Tsai TF (2020) Mitochondria and calcium homeostasis: Cisd2 as a big player in cardiac ageing. Int J Mol Sci 21. https://doi.org/10.3390/ijms21239238
Yu H, Guo Y, Mi L et al (2011) Mitofusin 2 inhibits angiotensin II-induced myocardial hypertrophy. J Cardiovasc Pharmacol Ther 16:205–211. https://doi.org/10.1177/1074248410385683
Yu H, Zhang F, Yan P et al (2021) LARP7 protects against heart failure by enhancing mitochondrial biogenesis. Circulation 143:2007–2022. https://doi.org/10.1161/circulationaha.120.050812
Yu Y, Peng XD, Qian XJ et al (2021) Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis. Signal Transduct Target Ther 6:401. https://doi.org/10.1038/s41392-021-00790-2
Zhang Y, Wang Y, Xu J et al (2019) Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways. J Pineal Res 66:e12542. https://doi.org/10.1111/jpi.12542
Zhao L, Zhuang J, Wang Y et al (2019) Propofol ameliorates H9c2 cells apoptosis induced by oxygen glucose deprivation and reperfusion injury via inhibiting high levels of mitochondrial fusion and fission. Front Pharmacol 10:61. https://doi.org/10.3389/fphar.2019.00061
Zhou H, Li D, Zhu P et al (2017) Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARgamma/FUNDC1/mitophagy pathways. J Pineal Res 63. https://doi.org/10.1111/jpi.12438
Zhou H, Ren J, Toan S, Mui D (2021) Role of mitochondrial quality surveillance in myocardial infarction: from bench to bedside. Ageing Res Rev 66(101250). https://doi.org/10.1016/j.arr.2020.101250
Zhou H, Wang J, Zhu P et al (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Res Cardiol 113:23. https://doi.org/10.1007/s00395-018-0682-1
Zhou H, Wang J, Zhu P et al (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol 113:23. https://doi.org/10.1007/s00395-018-0682-1
Zhou H, Zhu P, Wang J, Toan S, Ren J (2019) DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy. Signal Transduct Target Ther 4:56. https://doi.org/10.1038/s41392-019-0094-1
Zou R, Shi W, Qiu J et al (2022) Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis. Cardiovasc Diabetol 21:106. https://doi.org/10.1186/s12933-022-01532-6
Zunino R, Braschi E, Xu L, McBride HM (2009) Translocation of SenP5 from the nucleoli to the mitochondria modulates DRP1-dependent fission during mitosis. J Biol Chem 284:17783–17795. https://doi.org/10.1074/jbc.M901902200
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This study is supported by the Key R&D Program of the People’s Republic of China (2019YFC1711700).
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Xinxin Liu contributed to the review writing, Chenchen Guo contributed to the article collection, and Qiming Zhang contributed to the manuscript revision. All the authors approved this submission.
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Liu, X., Guo, C. & Zhang, Q. Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies. Cell Stress and Chaperones 28, 133–144 (2023). https://doi.org/10.1007/s12192-023-01321-4
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DOI: https://doi.org/10.1007/s12192-023-01321-4