A look at MERCs as UPR^mt regulatory hubs in age-associated heart diseases

Abstract

With the increase in life expectancy globally, the challenge of dealing with aging becomes more prominent. Aging is a risk factor for several diseases, including cardiovascular disease. Mitochondria, which have long been studied in relation to aging, play a crucial role in maintaining cellular homeostasis. However, there is a limitation in interorganellar communication as organisms age. The unfolded protein response in mitochondria (UPR^mt) is activated during stress to maintain mitochondrial homeostasis and prevent the accumulation of damaged mitochondria. This response involves signaling from the mitochondria to the nucleus, leading to transcriptional changes. In the context of aging heart, this review explores the role of mitochondria in terms of function and morphology. It also discusses the impact of UPR^mt on cardiac diseases such as heart failure, acute myocardial infarction, and dilated cardiomyopathy. The review also highlights the potential role of mitochondria-endoplasmic reticulum contact sites (MERCs) in modulating UPR^mt during aging. Finally, it provides an update on molecules that induce UPR^mt activity, potentially benefiting the aging heart with cardiac disease.

Keywords

Unfolded protein response-mitochondrial / cardiovascular diseases / aging / contactology / mitochondria-ER contact sites / longevity

References

[1] Sheng Y,Markovich Z,Xiao R.Distinct temporal actions of different types of unfolded protein responses during aging.J Cell Physiol2021;236:5069-79 PMCID:PMC8026671

[2] Kohler A.Better together: interorganellar communication in the regulation of proteostasis.Contact2024;7:25152564241272245 PMCID:PMC11462569

[3] Dana AH.Role of sulforaphane in endoplasmic reticulum homeostasis through regulation of the antioxidant response.Life Sci2022;299:120554

[4] Li Y,Jia L.LonP1 links mitochondria-ER interaction to regulate heart function.Research2023;6:0175 PMCID:PMC10275618

[5] Metzger MB.Analysis of quality control substrates in distinct cellular compartments reveals a unique role for Rpn4p in tolerating misfolded membrane proteins.Mol Biol Cell2009;20:1006-19 PMCID:PMC2633399

[6] Ciplys E,Juozapaitis M,Slibinskas R.Overexpression of human virus surface glycoprotein precursors induces cytosolic unfolded protein response in Saccharomyces cerevisiae.Microb Cell Fact2011;10:37 PMCID:PMC3120639

[7] Nunnari J.Mitochondria: in sickness and in health.Cell2012;148:1145-59 PMCID:PMC5381524

[8] Cilleros-Holgado P,Piñero-Pérez R.mtUPR modulation as a therapeutic target for primary and secondary mitochondrial diseases.Int J Mol Sci2023;24:1482 PMCID:PMC9865803

[9] Ali MA,Yang D,Tyrrell DJ.Cardiovascular aging: spotlight on mitochondria.Am J Physiol Heart Circ Physiol2024;326:H317-33 PMCID:PMC11219063

[10] Eckl EM,Krumwiede L,Jae LT.Sensing, signaling and surviving mitochondrial stress.Cell Mol Life Sci2021;78:5925-51 PMCID:PMC8316193

[11] Wang YT,McCall MN.Cardioprotection by the mitochondrial unfolded protein response requires ATF5.Am J Physiol Heart Circ Physiol2019;317:H472-8 PMCID:PMC6732477

[12] Bar-Ziv R,Hruby A.Glial-derived mitochondrial signals affect neuronal proteostasis and aging.Sci Adv2023;9:eadi1411 PMCID:PMC10575585

[13] Angeli S,Chamoli M.The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.Elife2021;10:e63453 PMCID:PMC8410078

[14] Evangelou K,Papaspyropoulos A.Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem.Physiol Rev2023;103:609-47

[15] Zhang W,Tang X.A biomarker framework for cardiac aging: the Aging Biomarker Consortium consensus statement.Life Med2023;2:lnad035

[16] Csordás G,Hajnóczky G.Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions.Trends Cell Biol2018;28:523-40 PMCID:PMC6005738

[17] Voeltz GK,Hajnóczky G.Making the connection: How membrane contact sites have changed our view of organelle biology.Cell2024;187:257-70

[18] He H,Wu X.Higher matrix stiffness promotes VSMC senescence by affecting mitochondria-ER contact sites and mitochondria/ER dysfunction.FASEB J2023;37:e23318

[19] Maddison DC,Amadio L.COPI-regulated mitochondria-ER contact site formation maintains axonal integrity.Cell Rep2023;42:112883 PMCID:PMC10840514

[20] Hinton A Jr,Mungai M.ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.J Cell Physiol2024;239:e31204

[21] Janer A,Krols M.ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.Life Sci Alliance2024;7:e202302335

[22] Garcia BM,Carvalho KF.Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis.Mol Hum Reprod2020;26:938-52

[23] Ziegler DV,Bernard D.Cellular senescence links mitochondria-ER contacts and aging.Commun Biol2021;4:1323 PMCID:PMC8613202

[24] Silva-Palacios A,Pedraza-Chaverri J.ER membranes associated with mitochondria: possible therapeutic targets in heart-associated diseases.Pharmacol Res2020;156:104758

[25] Casas-Martinez JC,McDonagh B.Redox regulation of UPR signalling and mitochondrial ER contact sites.Cell Mol Life Sci2024;81:250 PMCID:PMC11335286

[26] Moqri M,Poganik JR.Biomarkers of aging for the identification and evaluation of longevity interventions.Cell2023;186:3758-75 PMCID:PMC11088934

[27] Bao H,Chen M.Aging Biomarker ConsortiumBiomarkers of aging.Sci China Life Sci2023;66:893-1066

[28] Sierra F.Geroscience and the trans-NIH Geroscience Interest Group, GSIG.Geroscience2017;39:1-5 PMCID:PMC5352582

[29] López-Otín C,Partridge L,Kroemer G.Hallmarks of aging: an expanding universe.Cell2023;186:243-78

[30] López-Otín C,Partridge L,Kroemer G.The hallmarks of aging.Cell2013;153:1194-217 PMCID:PMC3836174

[31] Gil-Hernández A.Relevance of endoplasmic reticulum and mitochondria interactions in age-associated diseases.Ageing Res Rev2020;64:101193

[32] Camacho-Encina M,Redgrave RE,Spyridopoulos I.Cellular senescence, mitochondrial dysfunction, and their link to cardiovascular disease.Cells2024;13:353 PMCID:PMC10886919

[33] Guo J,Dou L.Aging and aging-related diseases: from molecular mechanisms to interventions and treatments.Signal Transduct Target Ther2022;7:391 PMCID:PMC9755275

[34] Xu M,Farr JN.Senolytics improve physical function and increase lifespan in old age.Nat Med2018;24:1246-56

[35] Jia K,Liu A.Senolytic agent navitoclax inhibits angiotensin II-induced heart failure in mice.J Cardiovasc Pharmacol2020;76:452-60

[36] Sunderland P,Ambrose E,Ellison-hughes GM.Senolytics rejuvenate the reparative activity of human cardiomyocytes and endothelial cells.J Cardiovasc Aging2023;3:21

[37] Vue Z,Vang L.Three-dimensional mitochondria reconstructions of murine cardiac muscle changes in size across aging.Am J Physiol Heart Circ Physiol2023;325:H965-82

[38] Tang X,Chen HZ.Cardiomyocyte senescence and cellular communications within myocardial microenvironments.Front Endocrinol2020;11:280 PMCID:PMC7253644

[39] Paneni F,Libby P,Camici GG.The aging cardiovascular system: understanding it at the cellular and clinical levels.J Am Coll Cardiol2017;69:1952-67

[40] Lu X,Hu W.Ultrastructural and proteomic profiling of mitochondria-associated endoplasmic reticulum membranes reveal aging signatures in striated muscle.Cell Death Dis2022;13:296 PMCID:PMC8976840

[41] Nieto M,Silva-Palacios A.Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease.Biogerontology2024;25:71-82

[42] Charles AL,Vogel T.Cumulative deleterious effects of tetrahydrocannabinoid (THC) and ethanol on mitochondrial respiration and reactive oxygen species production are enhanced in old isolated cardiac mitochondria.Int J Mol Sci2024;25:1835 PMCID:PMC10855679

[43] Rosa FLL,Monnerat G,Maciel L.Aging triggers mitochondrial dysfunction in mice.Int J Mol Sci2023;24:10591 PMCID:PMC10342046

[44] Schaum N,Hahn O.Ageing hallmarks exhibit organ-specific temporal signatures.Nature2020;583:596-602

[45] Sarver DC,Chen F.Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.Elife2024;13:e96926 PMCID:PMC11661797

[46] Muris Consortium. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse.Nature2020;583:590-5

[47] Zhang MJ,Darmanis S.Mouse aging cell atlas analysis reveals global and cell type-specific aging signatures.Elife2021;10:62293 PMCID:PMC8046488

[48] Lehallier B,Schaum N.Undulating changes in human plasma proteome profiles across the lifespan.Nat Med2019;25:1843-50 PMCID:PMC7062043

[49] Oh HS,Nachun D.Organ aging signatures in the plasma proteome track health and disease.Nature2023;624:164-72 PMCID:PMC10700136

[50] Lesnefsky EJ,Hoppel CL.Mitochondrial metabolism in aging heart.Circ Res2016;118:1593-611 PMCID:PMC5009371

[51] Fannin SW,Slabe TJ,Hoppel CL.Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria.Arch Biochem Biophys1999;372:399-407

[52] García-Niño WR,Rodríguez-Barrena JI.Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures.Basic Res Cardiol2017;112:15

[53] Lesnefsky EJ,Moghaddas S.Aging decreases electron transport complex III activity in heart interfibrillar mitochondria by alteration of the cytochrome c binding site.J Mol Cell Cardiol2001;33:37-47

[54] Chen Q,Hu Y.Aging-induced mitochondrial dysfunction: two distinct populations of mitochondria versus a combined population.Am J Physiol Heart Circ Physiol2024;326:H385-95 PMCID:PMC11219051

[55] Cogliati S,Scorrano L.Mitochondrial cristae: where beauty meets functionality.Trends Biochem Sci2016;41:261-73

[56] Morris S,Molina-Riquelme I.Decreased ATP synthase activity is linked to altered spatiotemporal organisation of ATP Synthase in a cellular cardiomyocyte senescent model. bioRxiv 2024.

[57] Wang G,Hu J,Liu X.Effects of aging on expression of Mic60 and OPA1 and mitochondrial morphology in myocardium of Tibetan sheep.Animals2020;10:2160 PMCID:PMC7699535

[58] Morris S,Barrientos G.Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.Biochim Biophys Acta Bioenergy2023;1864:148949

[59] Crabtree A,Marshall AG.Defining mitochondrial cristae morphology changes induced by aging in brown adipose tissue.Adv Biol2024;8:e2300186

[60] Campbell D.The mechanisms and roles of mitochondrial dynamics in C. elegans.Semin Cell Dev Biol2024;156:266-75

[61] Mokhtari B,Høilund-Carlsen PF,Rajabi M.The additive effects of nicotinamide mononucleotide and melatonin on mitochondrial biogenesis and fission/fusion, autophagy, and microRNA-499 in the aged rat heart with reperfusion injury.Naunyn Schmiedebergs Arch Pharmacol2023;396:1701-11

[62] Chaudhari SN.Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways.Nat Commun2017;8:182 PMCID:PMC5541002

[63] Liu YJ,Janssens GE.Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30.J Cell Biol2020;219:e201907067

[64] Cai Y,Weng H.Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP⁺ in human SH-SY5Y neuroblastoma cells.Sci Rep2020;10:10444 PMCID:PMC7320005

[65] Bomer N,Deiman FE.Selenoprotein DIO2 is a regulator of mitochondrial function, morphology and UPRmt in human cardiomyocytes.Int J Mol Sci2021;22:11906 PMCID:PMC8584701

[66] Mone P,Morciano G.Dysfunctional mitochondria elicit bioenergetic decline in the aged heart.J Cardiovasc Aging2024;4:13 PMCID:PMC11250775

[67] Guo Z,Ying X.Caloric restriction increases the resistance of aged heart to myocardial ischemia/reperfusion injury via modulating AMPK-SIRT₁-PGC_1a energy metabolism pathway.Sci Rep2023;13:2045 PMCID:PMC9899227

[68] Shen G,Xu L.Mitochondrial unfolded protein response and its roles in stem cells.Stem Cells Dev2020;29:627-37

[69] Yoneda T,Urano F,Harding HP.Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones.J Cell Sci2004;117:4055-66

[70] Nargund AM,Fiorese CJ,Haynes CM.Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation.Science2012;337:587-90 PMCID:PMC3518298

[71] Mouchiroud L,Moullan N.The NAD⁺/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.Cell2013;154:430-41 PMCID:PMC3753670

[72] Bennett CF,Simko M.Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans.Nat Commun2014;5:3483 PMCID:PMC3984390

[73] Zhao Q,Levichkin IV,Ryan MT.A mitochondrial specific stress response in mammalian cells.EMBO J2002;21:4411-9 PMCID:PMC126185

[74] Maragkakis M,Hatzoglou M.Biology of stress responses in aging.Aging Biol2023;1:20230001 PMCID:PMC10947073

[75] Lionaki E.Oxidative stress and mitochondrial protein quality control in aging.J Proteomics2013;92:181-94

[76] Torres AK,Inestrosa NC.Mitochondrial unfolded protein response (UPR^mt): what we know thus far.Front Cell Dev Biol2024;12:1405393 PMCID:PMC11176431

[77] Zhu D,Tian Y.Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.Trends Biochem Sci2022;47:645-59

[78] Jovaisaite V,Auwerx J.The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease.J Exp Biol2014;217:137-43 PMCID:PMC3867496

[79] Horibe T.The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response.PLoS One2007;2:e835 PMCID:PMC1950685

[80] Aldridge JE,Hoogenraad NJ.Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements.PLoS One2007;2:e874 PMCID:PMC1964532

[81] Zhou H,Gao W.Loss of high-temperature requirement protein A2 protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia.IUBMB Life2020;72:1659-79

[82] Ristow M.Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits.Nat Med2014;20:709-11

[83] Rolland SG,Schwarz M.Compromised mitochondrial protein import acts as a signal for UPR^mt.Cell Rep2019;28:1659-69.e5

[84] Lee MJ,Zhu J.Auraptene enhances junction assembly in cerebrovascular endothelial cells by promoting resilience to mitochondrial stress through activation of antioxidant enzymes and mtUPR.Antioxidants2021;10:475 PMCID:PMC8002628

[85] Pulliam DA,Liu Y.Complex IV-deficient Surf1^-/- mice initiate mitochondrial stress responses.Biochem J2014;462:359-71 PMCID:PMC4145821

[86] Owusu-Ansah E,Perrimon N.Muscle mitohormesis promotes longevity via systemic repression of insulin signaling.Cell2013;155:699-712 PMCID:PMC3856681

[87] Zhao K,Zhao W,Yang Z.LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.Development2022;149:dev200458

[88] Zhang C,Xu L.LONP1 alleviates ageing-related renal fibrosis by maintaining mitochondrial homeostasis.J Cell Mol Med2024;28:e70090 PMCID:PMC11390342

[89] Meng J,Guo M.A Lycium barbarum extract inhibits β-amyloid toxicity by activating the antioxidant system and mtUPR in a Caenorhabditis elegans model of Alzheimer's disease.FASEB J2022;36:e22156

[90] Papa L.SirT3 regulates the mitochondrial unfolded protein response.Mol Cell Biol2014;34:699-710 PMCID:PMC3911493

[91] Shpilka T.The mitochondrial UPR: mechanisms, physiological functions and implications in ageing.Nat Rev Mol Cell Biol2018;19:109-20

[92] Xu WN,Yang RZ.The mitochondrial UPR induced by ATF5 attenuates intervertebral disc degeneration via cooperating with mitophagy.Cell Biol Toxicol2024;40:16 PMCID:PMC10933207

[93] Ito A,Tanaka Y.Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans.Biogerontology2021;22:119-31

[94] Wu J,Zhang W.Emerging role of SIRT3 in mitochondrial dysfunction and cardiovascular diseases.Free Radic Res2019;53:139-49

[95] Zhang B,Zhang Z.Novel PGC-1α/ATF5 axis partly activates UPR^mt and mediates cardioprotective role of tetrahydrocurcumin in pathological cardiac hypertrophy.Oxid Med Cell Longev2020;2020:9187065 PMCID:PMC7781724

[96] Chen S,Petriello MC.Trimethylamine N-Oxide binds and activates PERK to promote metabolic dysfunction.Cell Metab2019;30:1141-51.e5

[97] Brunt VE,Casso AG.Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans.Hypertension2020;76:101-12 PMCID:PMC7295014

[98] An H,Hayakawa K.ATF5-mediated mitochondrial unfolded protein response (UPR^mt) protects neurons against oxygen-glucose deprivation and cerebral ischemia.Stroke2024;55:1904-13

[99] Guo Q,Zhou D.Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.Sci Adv2022;8:eabo0340 PMCID:PMC9328690

[100] Deng J,Shi Y.Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.Biomed Pharmacother2024;177:116989

[101] Hinton A Jr,Neikirk K.Mitochondrial structure and function in human heart failure.Circ Res2024;135:372-96 PMCID:PMC11225798

[102] Sun J,Guo Y.Sex differences in characteristics and outcomes in elderly heart failure patients with preserved ejection fraction: a post-hoc analysis from TOPCAT.Front Cardiovasc Med2021;8:721850 PMCID:PMC8520937

[103] Gharagozloo K,Heckman G.Heart failure with preserved ejection fraction in the elderly population: basic mechanisms and clinical considerations.Can J Cardiol2024;40:1424-44

[104] Hoshino A,Ariyoshi M.Oxidative post-translational modifications develop LONP1 dysfunction in pressure overload heart failure.Circ Heart Fail2014;7:500-9

[105] Bozi LH,Rolim N.Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats.J Cell Mol Med2016;20:2208-12 PMCID:PMC5082404

[106] Schiattarella GG,Tong D.Nitrosative stress drives heart failure with preserved ejection fraction.Nature2019;568:351-6 PMCID:PMC6635957

[107] Kitakata H,Hashimoto S.Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress.Biochem Biophys Res Commun2021;572:185-90

[108] Smyrnias I,Okonko DO.Cardioprotective effect of the mitochondrial unfolded protein response during chronic pressure overload.J Am Coll Cardiol2019;73:1795-806 PMCID:PMC6456800

[109] 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

[110] Pryde KR,Schapira AH.A LON-ClpP Proteolytic axis degrades complex I to extinguish ROS production in depolarized mitochondria.Cell Rep2016;17:2522-31 PMCID:PMC5177631

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

[112] Fan F,Yang F.Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure.Cell Death Differ2020;27:587-600 PMCID:PMC7205885

[113] Svagusa T,Milavic M.Heart failure in patients is associated with downregulation of mitochondrial quality control genes.Eur J Clin Invest2023;53:e14054

[114] Mirosevic V,Matic N.Cardiotoxicity of iron and zinc and their association with the mitochondrial unfolded protein response in humans.Int J Mol Sci2024;25:9648 PMCID:PMC11395499

[115] Damluji AA,Katz JN.Mechanical complications of acute myocardial infarction: a scientific statement from the American heart association.Circulation2021;144:e16-35 PMCID:PMC9364424

[116] Liu G,Lv X,Li J.Identification of mitochondria-related gene biomarkers associated with immune infiltration in acute myocardial infarction.iScience2024;27:110275 PMCID:PMC11261152

[117] Arroyo-Campuzano M,Silva-Palacios A.Cardiosome-mediated protection in myocardial ischemia.Clin Chim Acta2023;545:117374

[118] Mariani J,Bailey M.Tolerance to ischemia and hypoxia is reduced in aged human myocardium.J Thorac Cardiovasc Surg2000;120:660-7

[119] Venkatesh S,Saito T.Mitochondrial LonP1 protects cardiomyocytes from ischemia/reperfusion injury in vivo.J Mol Cell Cardiol2019;128:38-50

[120] Ji H,Muid D,Jiang Y.FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.Cell Signal2022;92:110249

[121] Lee CK,Weindruch R.Gene expression profile of aging and its retardation by caloric restriction.Science1999;285:1390-3

[122] Bronikowski AM,Morgan TJ.Lifelong voluntary exercise in the mouse prevents age-related alterations in gene expression in the heart.Physiol Genomics2003;12:129-38

[123] Rojas-Morales P,Granados-Pineda J.Protection against renal ischemia and reperfusion injury by short-term time-restricted feeding involves the mitochondrial unfolded protein response.Free Radic Biol Med2020;154:75-83

[124] Wang K,Liu J.Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death: Omi/HtrA2 and aged heart injury.Age2013;35:733-46 PMCID:PMC3636415

[125] Li X,Zeng Z.Serum albumin and prognosis in elderly patients with nonischemic dilated cardiomyopathy.J Cardiovasc Med2023;24:752-7

[126] Jin L,Ying L.FGF21-sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity.Circulation2022;146:1537-57

[127] Nandi SS,Mahata SK.Neurogenic hypertension mediated mitochondrial abnormality leads to cardiomyopathy: contribution of UPR^mt and Norepinephrine-miR-18a-5p-HIF-1α Axis.Front Physiol2021;12:718982 PMCID:PMC8667690

[128] Tezze C,Desbats MA.Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence.Cell Metab2017;25:1374-89.e6 PMCID:PMC5462533

[129] Ahola S,Mayer F.Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.Sci Adv2024;10:eadp0443 PMCID:PMC11296347

[130] Seiferling D,Becker C.Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.EMBO Rep2016;17:953-64 PMCID:PMC4931557

[131] Longhitano L,Musso N.(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease.J Transl Med2024;22:82 PMCID:PMC10799515

[132] Xiaowei X,Dingzhou Z.Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.Int J Biol Sci2023;19:4327-39 PMCID:PMC10496505

[133] Barcena ML,Haritonow N.Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner.Aging2020;12:24117-33 PMCID:PMC7762497

[134] Dikalova AE,Xiao L.Mitochondrial deacetylase Sirt3 reduces vascular dysfunction and hypertension while Sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress.Circ Res2020;126:439-52

[135] Nichtová Z,De La Fuente S.Enhanced mitochondria-SR tethering triggers adaptive cardiac muscle remodeling.Circ Res2023;132:e171-87 PMCID:PMC10213149

[136] Bosc C,Fanjul M.Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites.Nat Commun2020;11:4056 PMCID:PMC7426880

[137] Ching C,di Cicco A,Dezi M.Cool-contacts: cryo-electron microscopy of membrane contact sites and their components.Contact2024;7:25152564241231364 PMCID:PMC10895918

[138] Li Y,Yu Q.Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-Mitochondria miscommunication in the liver of HFD mice.Biomed Pharmacother2024;175:116682

[139] Sun Y,Qian S,Zang QS.Beclin-1 improves mitochondria-associated membranes in the heart during endotoxemia.FASEB Bioadv2021;3:123-35 PMCID:PMC7944875

[140] McCandless MG,Booz GW.What role do mitochondria have in diastolic dysfunction? Implications for diabetic cardiomyopathy and heart failure with preserved ejection function.J Cardiovasc Pharmacol2022;79:399-406

[141] Ren L,Perkins G.Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.Proc Natl Acad Sci USA2022;119:e2206708119 PMCID:PMC9456763

[142] Zhang P,Zhang Y.Clusterin is involved in mediating the metabolic function of adipose SIRT1.iScience2022;25:103709 PMCID:PMC8762396

[143] Chen R,Wang Y.Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response.Toxicol Appl Pharmacol2024;491:117072

[144] Li H,Zhang X.Screening of an FDA-approved compound library identifies apigenin for the treatment of myocardial injury.Int J Biol Sci2023;19:5233-44 PMCID:PMC10620826

[145] Dong X,Wen RJ.Xinyang tablet alleviated cardiac dysfunction in a cardiac pressure overload model by regulating the receptor-interacting serum/three-protein kinase 3/FUN14 domain containing 1-mediated mitochondrial unfolded protein response and mitophagy.J Ethnopharmacol2024;330:118152

[146] Sun JM,Liu YD.Salvianolic acid B protects against UVB-induced skin aging via activation of NRF2.Phytomedicine2024;130:155676

[147] Ma X,Zhang Z.Salvianolic acid B ameliorates cognitive deficits through IGF-1/Akt pathway in rats with vascular dementia.Cell Physiol Biochem2017;43:1381-91

[148] Wang D,Zou X,Zheng Z.Antioxidant apigenin relieves age-related muscle atrophy by inhibiting oxidative stress and hyperactive mitophagy and apoptosis in skeletal muscle of mice.J Gerontol A Biol Sci Med Sci2020;75:2081-8 PMCID:PMC7566467

[149] Yao X,Li YH.Apigenin delays postovulatory oocyte aging by reducing oxidative stress through SIRT1 upregulation.Theriogenology2024;218:89-98

[150] Ma Y,Zhang Y.Apigenin and baicalein ameliorate thoracic aortic structural deterioration and cognitive deficit via inhibiting AGEs/RAGE/NF-κB pathway in D-galactose-induced aging rats.Eur J Pharmacol2024;976:176660

[151] Wang Y,Li X.Preclinical evidence and possible mechanisms of baicalein for rats and mice with parkinson's disease: a systematic review and meta-analysis.Front Aging Neurosci2020;12:277 PMCID:PMC7546397

[152] Cai P,Yin Z,Zhou X.Baicalein ameliorates osteoporosis via AKT/FOXO1 signaling.Aging2021;13:17370-9 PMCID:PMC8312461

[153] Guo L,Yuan W.Baicalein ameliorated obesity-induced cardiac dysfunction by regulating the mitochondrial unfolded protein response through NRF2 signaling.Phytomedicine2024;126:155441

[154] Shi L,Zheng W.CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.Cell Death Discov2024;10:53 PMCID:PMC10817931

[155] Chang X,Liu J.Zishen Tongyang Huoxue decoction (TYHX) alleviates sinoatrial node cell ischemia/reperfusion injury by directing mitochondrial quality control via the VDAC1-β-tubulin signaling axis.J Ethnopharmacol2024;320:117371

[156] Chang X,Huang Y.Quercetin inhibits necroptosis in cardiomyocytes after ischemia-reperfusion via DNA-PKcs-SIRT5-orchestrated mitochondrial quality control.Phytother Res2024;38:2496-517

[157] Xu M,He X.Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.FASEB J2024;38:e23654

[158] Xu M,Lu Y.Choline ameliorates cardiac hypertrophy by regulating metabolic remodelling and UPRmt through SIRT3-AMPK pathway.Cardiovasc Res2019;115:530-45