Heart failure in patients is associated with downregulation of mitochondrial quality control genes.
MQC
TIM
UPRmt
heart
mitochondria
mitophagy
Journal
European journal of clinical investigation
ISSN: 1365-2362
Titre abrégé: Eur J Clin Invest
Pays: England
ID NLM: 0245331
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
revised:
27
05
2023
received:
19
02
2023
accepted:
15
06
2023
pubmed:
5
7
2023
medline:
5
7
2023
entrez:
5
7
2023
Statut:
ppublish
Résumé
Mitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure. Myocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real-time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion-fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry. The following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT-ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM. Heart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion-fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.
Sections du résumé
BACKGROUND
BACKGROUND
Mitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure.
METHODS
METHODS
Myocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real-time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion-fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry.
RESULTS
RESULTS
The following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT-ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM.
CONCLUSIONS
CONCLUSIONS
Heart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion-fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14054Subventions
Organisme : NIH HHS
ID : U420D11158
Pays : United States
Organisme : NIH HHS
ID : U420D11158
Pays : United States
Informations de copyright
© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.
Références
Svaguša T, Martinić M, Martinić M, et al. Mitochondrial unfolded protein response, mitophagy and other mitochondrial quality control mechanisms in heart disease and aged heart. Croat Med J. 2020;61(2):126-138.
Briceno N, Schuster A, Lumley M, Perera D. Ischaemic cardiomyopathy: pathophysiology, assessment and the role of revascularisation. Heart (British Cardiac Society). 2016;102(5):397-406.
Chang X, Toan S, Li R, Zhou H. Therapeutic strategies in ischemic cardiomyopathy: focus on mitochondrial quality surveillance. EBioMedicine. 2022;84:104260.
Jefferies JL, Towbin JA. Dilated cardiomyopathy. Lancet (London, England). 2010;375(9716):752-762.
Seferović PM, Polovina M, Bauersachs J, et al. Heart failure in cardiomyopathies: a position paper from the heart failure Association of the European Society of cardiology. Eur J Heart Fail. 2019;21(5):553-576.
Venditti P, Di Stefano L, Di Meo S. Mitochondrial metabolism of reactive oxygen species. Mitochondrion. 2013;13(2):71-82.
Inigo JR, Chandra D. The mitochondrial unfolded protein response (UPRmt): shielding against toxicity to mitochondria in cancer. J Hematol Oncol. 2022;15(1):98.
Rainbolt TK, Atanassova N, Genereux JC, Wiseman RL. Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell Metab. 2013;18(6):908-919.
Chang X, Lochner A, Wang HH, et al. Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control. Theranostics. 2021;11(14):6766-6785.
Zhou H, Ren J, Toan S, Mui D. Role of mitochondrial quality surveillance in myocardial infarction: from bench to bedside. Ageing Res Rev. 2021;66:101250.
Kuo CY, Chiu YC, Lee AYL, Hwang TL. Mitochondrial Lon protease controls ROS-dependent apoptosis in cardiomyocyte under hypoxia. Mitochondrion. 2015;1(23):7-16.
Sedlic F, Seiwerth F, Sepac A, et al. Mitochondrial ROS induce partial dedifferentiation of human mesothelioma via upregulation of NANOG. Antioxidants (Basel, Switzerland). 2020;9(7):1-16.
Saito T, Hamano K, Sadoshima J. Molecular mechanisms and clinical implications of multiple forms of mitophagy in the heart. Cardiovasc Res. 2021;117(14):2730-2741.
Mottis A, Jovaisaite V, Auwerx J. The mitochondrial unfolded protein response in mammalian physiology. Mamm Genome. 2014;25(9-10):424-433.
Stotland A, Gottlieb RA. Mitochondrial quality control: easy come, easy go. Biochim Biophys Acta. 2015;1853(10 Pt B):2802-2811.
Rehling P, Brandner K, Pfanner N. Mitochondrial import and the twin-pore translocase. Nat Rev Mol Cell Biol. 2004;5(7):519-530.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402-408.
Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res. 2021;128(10):1487-1513.
Baandrup U, Florio RA, Roters F, Olsen EG. Electron microscopic investigation of endomyocardial biopsy samples in hypertrophy and cardiomyopathy. A semiquantitative study in 48 patients. Circulation. 1981;63(6):1289-1298.
Karamanlidis G, Nascimben L, Couper GS, Shekar PS, Del Monte F, Tian R. Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res. 2010;106(9):1541-1548.
Hoshino A, Okawa Y, Ariyoshi M, et al. Oxidative post-translational modifications develop LONP1 dysfunction in pressure overload heart failure. Circ Heart Fail. 2014;7(3):500-509.
García-Rúa V, Otero MF, Lear PV, et al. Increased expression of fatty-acid and calcium metabolism genes in failing human heart. PloS One. 2012;7(6):e37505.
Rowe GC, Jiang A, Arany Z. PGC-1 coactivators in cardiac development and disease. Circ Res. 2010;107(7):825-838.
Su T, Zhang Z, Han X, et al. Systematic insight of resveratrol activated SIRT1 Interactome through proximity labeling strategy. Antioxidants (Basel). 2022;11(12):2330.
de la Cruz López KG, Toledo Guzmán ME, Sánchez EO, García CA. mTORC1 as a regulator of mitochondrial functions and a therapeutic target in cancer. Front Oncol. 2019;9:1373.
Khan NA, Nikkanen J, Yatsuga S, et al. mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab. 2017;26(2):419-428.e5.
Gariani K, Menzies KJ, Ryu D, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology. 2016;63(4):1190-1204.
Wan W, Hua F, Fang P, et al. Regulation of Mitophagy by Sirtuin family proteins: a vital role in aging and age-related diseases. Front Aging Neurosci. 2022;14:845330.
Piquereau J, Caffin F, Novotova M, et al. Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload. Cardiovasc Res. 2012;94(3):408-417.
Ikeda Y, Shirakabe A, Maejima Y, et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. 2015;116(2):264-278.
Sadat A, Tiwari S, Sunidhi S, et al. Conserved and divergent chaperoning effects of Hsp60/10 chaperonins on protein folding landscapes. Proc Natl Acad Sci U S A. 2022;119(18):e2118465119.
Böttinger L, Oeljeklaus S, Guiard B, Rospert S, Warscheid B, Becker T. Mitochondrial heat shock protein (Hsp) 70 and Hsp10 cooperate in the formation of Hsp60 complexes. J Biol Chem. 2015;290(18):11611-11622.
Khalimonchuk O, Jeong MY, Watts T, Ferris E, Winge DR. Selective Oma1 protease-mediated proteolysis of Cox1 subunit of cytochrome oxidase in assembly mutants. J Biol Chem. 2012;287(10):7289-7300.
Leonhard K, Herrmann JM, Stuart RA, Mannhaupt G, Neupert W, Langer T. AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria. EMBO J. 1996;15(16):4218-4229.
Windak R, Müller J, Felley A, et al. The AP-1 transcription factor c-Jun prevents stress-imposed maladaptive remodeling of the heart. PLoS One. 2013;8(9):e73294.
Wai T, García-Prieto J, Baker MJ, et al. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2015;350(6265):aad0116-1-11.
Guo Y, Wang Z, Qin X, et al. Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart. Cardiovasc Res. 2018;114(7):979-991.
Fu HY, Okada KI, Liao Y, et al. Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. Circulation. 2010;122(4):361-369.
Wang K, Yuan Y, Liu X, et al. Cardiac specific overexpression of mitochondrial Omi/HtrA2 induces myocardial apoptosis and cardiac dysfunction. Sci Rep. 2016;7:6.
Sedlic F, Kovac Z. Non-linear actions of physiological agents: finite disarrangements elicit fitness benefits. Redox Biol. 2017;1(13):235-243.
Zhao F, Zou MH. Role of the mitochondrial protein import machinery and protein processing in heart disease. Front Cardiovasc Med. 2021;28:8.
Goto N, Kawamura M, Inoue M, Sato A. Pathology of two cases of canine disseminated hypereosinophilic disease. Nihon Juigaku Zasshi. 1983;45(3):305-312.
Chang X, Li Y, Cai C, et al. Mitochondrial quality control mechanisms as molecular targets in diabetic heart. Metabolism. 2022;137:155313.
Cang C, Zhou Y, Navarro B, et al. mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell. 2013;152(4):778-790.
Dorn GW. Mitochondrial pruning by nix and BNip3: an essential function for cardiac-expressed death factors. J Cardiovasc Transl Res. 2010;3(4):374-383.
Xie M, Cho GW, Kong Y, et al. Activation of autophagic flux blunts cardiac ischemia/reperfusion injury. Circ Res. 2021;129(3):435-450.
Barcena ML, Pozdniakova S, Haritonow N, et al. Dilated cardiomyopathy impairs mitochondrial biogenesis and promotes inflammation in an age- and sex-dependent manner. Aging. 2020;12(23):24117-24133.
Meyer-Roxlau S, Lämmle S, Opitz A, et al. Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation. Basic Res Cardiol. 2017;112(4):43.
Jensen BC, Bultman SJ, Holley D, et al. Upregulation of autophagy genes and the unfolded protein response in human heart failure. Int J Clin Exp Med. 2017;10(1):1051-1058.
Latif N, Taylor PM, Khan MA, Yacoub MH, Dunn MJ. The expression of heat shock protein 60 in patients with dilated cardiomyopathy. Basic Res Cardiol. 1999;94(2):112-119.
Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med. 2019;51(12):1-13.
Tampo A, Hogan CS, Sedlic F, Bosnjak ZJ, Kwok WM. Accelerated inactivation of cardiac L-type calcium channels triggered by anaesthetic-induced preconditioning. Br J Pharmacol. 2009;156(3):432-443.
Sedlic F, Sepac A, Pravdic D, et al. Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca2+. Am J Physiol Cell Physiol. 2010;299(2):C506-C515.
Canfield SG, Sepac A, Sedlic F, Muravyeva MY, Bai X, Bosnjak ZJ. Marked hyperglycemia attenuates anesthetic preconditioning in human-induced pluripotent stem cell-derived cardiomyocytes. Anesthesiology. 2012;117(4):735-744.