肥胖所致心肌重构及相关线粒体稳态失衡机制研究进展
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摘要
肥胖是心血管疾病的重要危险因素,可导致心肌重构等多种心血管疾病。肥胖可影响血流动力学、破坏自主神经平衡、诱导脂肪组织功能障碍和线粒体稳态失衡,从而损伤心肌功能。代谢稳态所需的关键生物化学反应主要发生在线粒体中,线粒体稳态是决定细胞活力的关键因素之一。线粒体稳态的平衡由线粒体分裂和融合、线粒体嵴重构、线粒体生物合成、线粒体自噬、线粒体氧化应激等动态过程调节。线粒体分裂和融合以及线粒体嵴形态不断变化以维持线粒体结构的完整性,且线粒体通过生物合成和自噬降解以维持"健康"的线粒体状态,而活性氧簇可作为信号分子调控细胞内信号转导。肥胖时的脂质过度沉积及脂质合成与分解不平衡诱发线粒体结构和功能的稳态失衡,激活细胞凋亡级联反应并导致心肌重塑。本文就肥胖所致心肌重构的可能机制以及线粒体稳态失衡在其中的重要作用作一简要综述,以期为临床上肥胖所致心血管疾病的防治提供重要策略和潜在靶点。
Obesity is an important risk factor for cardiovascular diseases, which can lead to a variety of cardiovascular diseases including myocardial remodeling. Obesity may induce myocardial dysfunction by affecting hemodynamics, inducing autonomic imbalance, adipose tissue dysfunction, and mitochondrial dyshomeostasis. The key necessary biochemical functions for metabolic homeostasis are performed in mitochondria, and mitochondrial homeostasis is considered as one of the key determinants for cell viability. Mitochondrial homeostasis is regulated by dynamic regulation of mitochondrial fission and fusion, as well as mitochondrial cristae remodeling, biogenesis, autophagy, and oxidative stress. The mitochondrial fission-fusion and morphological changes of mitochondrial cristae maintain the integrity of the mitochondrial structure. The mitochondria maintain a "healthy" state by balancing biogenesis and autophagy, while reactive oxygen species can act as signaling molecules to regulate intracellular signaling. The excessive accumulation of lipids and lipid metabolism disorder in obesity leads to mitochondrial dyshomeostasis, which activate the apoptotic cascade and lead to myocardial remodeling. In this review, we provide an overview of the recent research progress on obesity-induced myocardial remodeling and its possible mechanism of mitochondrial dyshomeostasis.
Obesity is an important risk factor for cardiovascular diseases, which can lead to a variety of cardiovascular diseases including myocardial remodeling. Obesity may induce myocardial dysfunction by affecting hemodynamics, inducing autonomic imbalance, adipose tissue dysfunction, and mitochondrial dyshomeostasis. The key necessary biochemical functions for metabolic homeostasis are performed in mitochondria, and mitochondrial homeostasis is considered as one of the key determinants for cell viability. Mitochondrial homeostasis is regulated by dynamic regulation of mitochondrial fission and fusion, as well as mitochondrial cristae remodeling, biogenesis, autophagy, and oxidative stress. The mitochondrial fission-fusion and morphological changes of mitochondrial cristae maintain the integrity of the mitochondrial structure. The mitochondria maintain a "healthy" state by balancing biogenesis and autophagy, while reactive oxygen species can act as signaling molecules to regulate intracellular signaling. The excessive accumulation of lipids and lipid metabolism disorder in obesity leads to mitochondrial dyshomeostasis, which activate the apoptotic cascade and lead to myocardial remodeling. In this review, we provide an overview of the recent research progress on obesity-induced myocardial remodeling and its possible mechanism of mitochondrial dyshomeostasis.
引文
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2 Aune D,Sen A,Norat T,Janszky I,Romundstad P,Tonstad S,Vatten LJ.Body mass index,abdominal fatness,and heart failure incidence and mortality:a systematic review and dose-response meta-analysis of prospective studies.Circulation 2016;133(7):639-649.
3 Azevedo PS,Polegato BF,Minicucci MF,Paiva SA,Zornoff LA.Cardiac remodeling:concepts,clinical impact,pathophysiological mechanisms and pharmacologic treatment.Arq Bras Cardiol 2016;106(1):62-69.
4 Bozkurt B,Aguilar D,Deswal A,Dunbar SB,Francis GS,Horwich T,Jessup M,Kosiborod M,Pritchett AM,Ramasubbu K,Rosendorff C,Yancy C;American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology;Council on Cardiovascular Surgery and Anesthesia;Council on Cardiovascular and Stroke Nursing;Council on Hypertension;and Council on Quality and Outcomes Research.Contributory risk and management of comorbidities of hypertension,obesity,diabetes mellitus,hyperlipidemia,and metabolic syndrome in chronic heart failure:a scientific statement from the american heart association.Circulation 2016;134(23):e535-e578.
5 Aurigemma GP,de Simone G,Fitzgibbons TP.Cardiac remodeling in obesity.Circ Cardiovasc Imaging 2013;6(1):142-152.
6 Abel ED,Litwin SE,Sweeney G.Cardiac remodeling in obesity.Physiol Rev 2008;88(2):389-419.
7 Lu Y,Wu Q,Liu LZ,Yu XJ,Liu JJ,Li MX,Zang WJ.Pyridostigmine protects against cardiomyopathy associated with adipose tissue browning and improvement of vagal activity in high-fat diet rats.Biochim Biophys Acta 2018;1864(4 Pt A):1037-1050.
8 Qin L,Zhao Y,Zhang B,Li Y.Amentoflavone improves cardiovascular dysfunction and metabolic abnormalities in high fructose and fat diet-fed rats.Food Funct 2018;9(1):243-252.
9 Packer M,Kitzman DW.Obesity-related heart failure with a preserved ejection fraction:the mechanistic rationale for combining inhibitors of aldosterone,neprilysin,and sodium-glucose cotransporter-2.JACC Heart Fail 2018;6(8):633-639.
10 Wehrwein EA,Orer HS,Barman SM.Overview of the anatomy,physiology,and pharmacology of the autonomic nervous system.Compr Physiol 2016;6(3):1239-1278.
11 Zhang Y,Ren J.Epigenetics and obesity cardiomyopathy:From pathophysiology to prevention and management.Pharmacol Ther 2016;161:52-66.
12 Thorp AA,Schlaich MP.Relevance of sympathetic nervous system activation in obesity and metabolic syndrome.JDiabetes Res 2015;2015:341583.
13 Banni S,Carta G,Murru E,Cordeddu L,Giordano E,Marrosu F,Puligheddu M,Floris G,Asuni GP,Cappai AL,Deriu S,Follesa P.Vagus nerve stimulation reduces body weight and fat mass in rats.PLoS One 2012;7(9):e44813.
14 Packer M.Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium.JAm Coll Cardiol 2018;71(20):2360-2372.
15 Shah RV,Anderson A,Ding J,Budoff M,Rider O,Petersen SE,Jensen MK,Koch M,Allison M,Kawel-Boehm N,Wisocky J,Jerosch-Herold M,Mukamal K,Lima JAC,Murthy VL.Pericardial,but not hepatic,fat by CT is associated with CV outcomes and structure:the multi-ethnic study of atherosclerosis.JACC Cardiovasc Imaging 2017;10(9):1016-1027.
16 Franssens BT,Nathoe HM,Leiner T,van der Graaf Y,Visseren FL;SMART study group.Relation between cardiovascular disease risk factors and epicardial adipose tissue density on cardiac computed tomography in patients at high risk of cardiovascular events.Eur J Prev Cardiol 2017;24(6):660-670.
17 Maximilian Buja L.Mitochondria in ischemic heart disease.Adv Exp Med Biol 2017;982:127-140.
18 Gambardella J,Sorriento D,Ciccarelli M,Del Giudice C,Fiordelisi A,Napolitano L,Trimarco B,Iaccarino G,Santulli G.Functional role of mitochondria in arrhythmogenesis.Adv Exp Med Biol 2017;982:191-202.
19 Xu S,Zhang X,Liu P.Lipid droplet proteins and metabolic diseases.Biochim Biophys Acta Mol Basis Dis 2018;1864(5Pt B):1968-1983.
20 D’Souza K,Nzirorera C,Kienesberger PC.Lipid metabolism and signaling in cardiac lipotoxicity.Biochim Biophys Acta 2016;1860(10):1513-1524.
21 Lindinger PW,Christe M,Eberle AN,Kern B,Peterli R,Peters T,Jayawardene KJ,Fearnley IM,Walker JE.Important mitochondrial proteins in human omental adipose tissue show reduced expression in obesity.J Proteomics 2015;124:79-87.
22 Jeong EM,Chung J,Liu H,Go Y,Gladstein S,Farzaneh-Far A,Lewandowski ED,Dudley SC Jr.Role of mitochondrial oxidative stress in glucose tolerance,insulin resistance,and cardiac diastolic dysfunction.J Am Heart Assoc 2016;5(5):e003046.
23 Torrealba N,Aranguiz P,Alonso C,Rothermel BA,Lavandero S.Mitochondria in structural and functional cardiac remodeling.Adv Exp Med Biol 2017;982:277-306.
24 Lesnefsky EJ,Chen Q,Hoppel CL.Mitochondrial metabolism in aging heart.Circ Res 2016;118(10):1593-1611.
25 Palikaras K,Tavernarakis N.Mitochondrial homeostasis:The interplay between mitophagy and mitochondrial biogenesis.Exp Gerontol 2014;56:182-188.
26 Roy M,Reddy PH,Iijima M,Sesaki H.Mitochondrial division and fusion in metabolism.Curr Opin Cell Biol 2015;33:111-118.
27 Cogliati S,Enriquez JA,Scorrano L.Mitochondrial cristae:where beauty meets functionality.Trends Biochem Sci 2016;41(3):261-273.
28 Pickles S,Vigie P,Youle RJ.Mitophagy and quality control mechanisms in mitochondrial maintenance.Curr Biol 2018;28(4):R170-R185.
29 Bertero E,Maack C.Calcium signaling and reactive oxygen species in mitochondria.Circ Res 2018;122(10):1460-1478.
30 Wai T,Langer T.Mitochondrial dynamics and metabolic regulation.Trends Endocrinol Metab 2016;27(2):105-117.
31 Pintus F,Floris G,Rufini A.Nutrient availability links mitochondria,apoptosis,and obesity.Aging(Albany NY)2012;4(11):734-741.
32 Tsushima K,Bugger H,Wende AR,Soto J,Jenson GA,Tor AR,McGlauflin R,Kenny HC,Zhang Y,Souvenir R,Hu XX,Sloan CL,Pereira RO,Lira VA,Spitzer KW,Sharp TL,Shoghi KI,Sparagna GC,Rog-Zielinska EA,Kohl P,Khalimonchuk O,Schaffer JE,Abel ED.Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121,DRP1,and OPA1 that promote mitochondrial fission.Circ Res 2018;122(1):58-73.
33 Aroor AR,Sowers JR,Bender SB,Nistala R,Garro M,Mugerfeld I,Hayden MR,Johnson MS,Salam M,Whaley-Connell A,Demarco VG.Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats.Endocrinology 2013;154(7):2501-2513.
34 Stacchiotti A,Favero G,Giugno L,Golic I,Korac A,Rezzani R.Melatonin efficacy in obese leptin-deficient mice heart.Nutrients 2017;9(12):E1323.
35 Whitaker RM,Corum D,Beeson CC,Schnellmann RG.Mitochondrial biogenesis as a pharmacological target:a new approach to acute and chronic diseases.Annu Rev Pharmacol Toxicol 2016;56:229-249.
36 Zhang Y,Xu H.Translational regulation of mitochondrial biogenesis.Biochem Soc Trans 2016;44(6):1717-1724.
37 Ren J,Pulakat L,Whaley-Connell A,Sowers JR.Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease.J Mol Med(Berl)2010;88(10):993-1001.
38 Neves FA,Cortez E,Bernardo AF,Mattos AB,Vieira AK,Malafaia Tde O,Thole AA,Rodrigues-Cunha AC,Garcia-Souza EP,Sichieri R,Moura AS.Heart energy metabolism impairment in Western-diet induced obese mice.J Nutr Biochem 2014;25(1):50-57.
39 Xu M,Xue RQ,Lu Y,Yong SY,Wu Q,Cui YL,Zuo XT,Yu XJ,Zhao M,Zang WJ.Choline ameliorates cardiac hypertrophy by regulating metabolic remodelling and UPRmt through SIRT3-AMPK pathway.Cardiovasc Res 2019;115(3):530-545.
40 Kubli DA,Gustafsson AB.Mitochondria and mitophagy:the yin and yang of cell death control.Circ Res 2012;111(9):1208-1221.
41 Okatsu K,Oka T,Iguchi M,Imamura K,Kosako H,Tani N,Kimura M,Go E,Koyano F,Funayama M,Shiba-Fukushima K,Sato S,Shimizu H,Fukunaga Y,Taniguchi H,Komatsu M,Hattori N,Mihara K,Tanaka K,Matsuda N.PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria.Nat Commun 2012;3:1016.
42 Saito T,Sadoshima J.Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart.Circ Res 2015;116(8):1477-1490.
43 Wu W,Xu H,Wang Z,Mao Y,Yuan L,Luo W,Cui Z,Cui T,Wang XL,Shen YH.PINK1-parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury.PLoS One 2015;10(7):e0132499.
44 Montgomery MK,Turner N.Mitochondrial dysfunction and insulin resistance:an update.Endocr Connect 2015;4(1):R1-R15.
45 Brown DA,Perry JB,Allen ME,Sabbah HN,Stauffer BL,Shaikh SR,Cleland JG,Colucci WS,Butler J,Voors AA,Anker SD,Pitt B,Pieske B,Filippatos G,Greene SJ,Gheorghiade M.Expert consensus document:Mitochondrial function as a therapeutic target in heart failure.Nat Rev Cardiol2017;14(4):238-250.
46 Marín-García J.Mitochondrial DNA repair:a novel therapeutic target for heart failure.Heart Fail Rev 2016;21(5):475-487.
47 Jacob SF,Würstle ML,Delgado ME,Rehm M.An analysis of the truncated Bid-and ROS-dependent spatial propagation of mitochondrial permeabilization waves during apoptosis.J Biol Chem 2016;291(9):4603-4613.
48 Sverdlov AL,Elezaby A,Qin F,Behring JB,Luptak I,Calamaras TD,Siwik DA,Miller EJ,Liesa M,Shirihai OS,Pimentel DR,Cohen RA,Bachschmid MM,Colucci WS.Mitochondrial reactive oxygen species mediate cardiac structural,functional,and mitochondrial consequences of diet-induced metabolic heart disease.J Am Heart Assoc2016;5(1):e002555.
49 Joseph LC,Barca E,Subramanyam P,Komrowski M,Pajvani U,Colecraft HM,Hirano M,Morrow JP.Inhibition of NAPDH oxidase 2(NOX2)prevents oxidative stress and mitochondrial abnormalities caused by saturated fat in cardiomyocytes.PLoS One 2016;11(1):e0145750.
50 Ilkun O,Wilde N,Tuinei J,Pires KM,Zhu Y,Bugger H,Soto J,Wayment B,Olsen C,Litwin SE,Abel ED.Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.J Mol Cell Cardiol 2015;85:104-116.
51 Lin YY,Hsieh PS,Cheng YJ,Cheng SM,Chen CJ,Huang CY,Kuo CH,Kao CL,Shyu WC,Lee SD.Anti-apoptotic and pro-survival effects of food restriction on high-fat diet-induced obese hearts.Cardiovasc Toxicol 2017;17(2):163-174.
52 Boardman NT,Hafstad AD,Lund J,Rossvoll L,Aasum E.Exercise of obese mice induces cardioprotection and oxygen sparing in hearts exposed to high-fat load.Am J Physiol Heart Circ Physiol 2017;313(5):H1054-H1062.
53 Cao K,Xu J,Pu W,Dong Z,Sun L,Zang W,Gao F,Zhang Y,Feng Z,Liu J.Punicalagin,an active component in pomegranate,ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation.Sci Rep 2015;5:14014.
2 Aune D,Sen A,Norat T,Janszky I,Romundstad P,Tonstad S,Vatten LJ.Body mass index,abdominal fatness,and heart failure incidence and mortality:a systematic review and dose-response meta-analysis of prospective studies.Circulation 2016;133(7):639-649.
3 Azevedo PS,Polegato BF,Minicucci MF,Paiva SA,Zornoff LA.Cardiac remodeling:concepts,clinical impact,pathophysiological mechanisms and pharmacologic treatment.Arq Bras Cardiol 2016;106(1):62-69.
4 Bozkurt B,Aguilar D,Deswal A,Dunbar SB,Francis GS,Horwich T,Jessup M,Kosiborod M,Pritchett AM,Ramasubbu K,Rosendorff C,Yancy C;American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology;Council on Cardiovascular Surgery and Anesthesia;Council on Cardiovascular and Stroke Nursing;Council on Hypertension;and Council on Quality and Outcomes Research.Contributory risk and management of comorbidities of hypertension,obesity,diabetes mellitus,hyperlipidemia,and metabolic syndrome in chronic heart failure:a scientific statement from the american heart association.Circulation 2016;134(23):e535-e578.
5 Aurigemma GP,de Simone G,Fitzgibbons TP.Cardiac remodeling in obesity.Circ Cardiovasc Imaging 2013;6(1):142-152.
6 Abel ED,Litwin SE,Sweeney G.Cardiac remodeling in obesity.Physiol Rev 2008;88(2):389-419.
7 Lu Y,Wu Q,Liu LZ,Yu XJ,Liu JJ,Li MX,Zang WJ.Pyridostigmine protects against cardiomyopathy associated with adipose tissue browning and improvement of vagal activity in high-fat diet rats.Biochim Biophys Acta 2018;1864(4 Pt A):1037-1050.
8 Qin L,Zhao Y,Zhang B,Li Y.Amentoflavone improves cardiovascular dysfunction and metabolic abnormalities in high fructose and fat diet-fed rats.Food Funct 2018;9(1):243-252.
9 Packer M,Kitzman DW.Obesity-related heart failure with a preserved ejection fraction:the mechanistic rationale for combining inhibitors of aldosterone,neprilysin,and sodium-glucose cotransporter-2.JACC Heart Fail 2018;6(8):633-639.
10 Wehrwein EA,Orer HS,Barman SM.Overview of the anatomy,physiology,and pharmacology of the autonomic nervous system.Compr Physiol 2016;6(3):1239-1278.
11 Zhang Y,Ren J.Epigenetics and obesity cardiomyopathy:From pathophysiology to prevention and management.Pharmacol Ther 2016;161:52-66.
12 Thorp AA,Schlaich MP.Relevance of sympathetic nervous system activation in obesity and metabolic syndrome.JDiabetes Res 2015;2015:341583.
13 Banni S,Carta G,Murru E,Cordeddu L,Giordano E,Marrosu F,Puligheddu M,Floris G,Asuni GP,Cappai AL,Deriu S,Follesa P.Vagus nerve stimulation reduces body weight and fat mass in rats.PLoS One 2012;7(9):e44813.
14 Packer M.Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium.JAm Coll Cardiol 2018;71(20):2360-2372.
15 Shah RV,Anderson A,Ding J,Budoff M,Rider O,Petersen SE,Jensen MK,Koch M,Allison M,Kawel-Boehm N,Wisocky J,Jerosch-Herold M,Mukamal K,Lima JAC,Murthy VL.Pericardial,but not hepatic,fat by CT is associated with CV outcomes and structure:the multi-ethnic study of atherosclerosis.JACC Cardiovasc Imaging 2017;10(9):1016-1027.
16 Franssens BT,Nathoe HM,Leiner T,van der Graaf Y,Visseren FL;SMART study group.Relation between cardiovascular disease risk factors and epicardial adipose tissue density on cardiac computed tomography in patients at high risk of cardiovascular events.Eur J Prev Cardiol 2017;24(6):660-670.
17 Maximilian Buja L.Mitochondria in ischemic heart disease.Adv Exp Med Biol 2017;982:127-140.
18 Gambardella J,Sorriento D,Ciccarelli M,Del Giudice C,Fiordelisi A,Napolitano L,Trimarco B,Iaccarino G,Santulli G.Functional role of mitochondria in arrhythmogenesis.Adv Exp Med Biol 2017;982:191-202.
19 Xu S,Zhang X,Liu P.Lipid droplet proteins and metabolic diseases.Biochim Biophys Acta Mol Basis Dis 2018;1864(5Pt B):1968-1983.
20 D’Souza K,Nzirorera C,Kienesberger PC.Lipid metabolism and signaling in cardiac lipotoxicity.Biochim Biophys Acta 2016;1860(10):1513-1524.
21 Lindinger PW,Christe M,Eberle AN,Kern B,Peterli R,Peters T,Jayawardene KJ,Fearnley IM,Walker JE.Important mitochondrial proteins in human omental adipose tissue show reduced expression in obesity.J Proteomics 2015;124:79-87.
22 Jeong EM,Chung J,Liu H,Go Y,Gladstein S,Farzaneh-Far A,Lewandowski ED,Dudley SC Jr.Role of mitochondrial oxidative stress in glucose tolerance,insulin resistance,and cardiac diastolic dysfunction.J Am Heart Assoc 2016;5(5):e003046.
23 Torrealba N,Aranguiz P,Alonso C,Rothermel BA,Lavandero S.Mitochondria in structural and functional cardiac remodeling.Adv Exp Med Biol 2017;982:277-306.
24 Lesnefsky EJ,Chen Q,Hoppel CL.Mitochondrial metabolism in aging heart.Circ Res 2016;118(10):1593-1611.
25 Palikaras K,Tavernarakis N.Mitochondrial homeostasis:The interplay between mitophagy and mitochondrial biogenesis.Exp Gerontol 2014;56:182-188.
26 Roy M,Reddy PH,Iijima M,Sesaki H.Mitochondrial division and fusion in metabolism.Curr Opin Cell Biol 2015;33:111-118.
27 Cogliati S,Enriquez JA,Scorrano L.Mitochondrial cristae:where beauty meets functionality.Trends Biochem Sci 2016;41(3):261-273.
28 Pickles S,Vigie P,Youle RJ.Mitophagy and quality control mechanisms in mitochondrial maintenance.Curr Biol 2018;28(4):R170-R185.
29 Bertero E,Maack C.Calcium signaling and reactive oxygen species in mitochondria.Circ Res 2018;122(10):1460-1478.
30 Wai T,Langer T.Mitochondrial dynamics and metabolic regulation.Trends Endocrinol Metab 2016;27(2):105-117.
31 Pintus F,Floris G,Rufini A.Nutrient availability links mitochondria,apoptosis,and obesity.Aging(Albany NY)2012;4(11):734-741.
32 Tsushima K,Bugger H,Wende AR,Soto J,Jenson GA,Tor AR,McGlauflin R,Kenny HC,Zhang Y,Souvenir R,Hu XX,Sloan CL,Pereira RO,Lira VA,Spitzer KW,Sharp TL,Shoghi KI,Sparagna GC,Rog-Zielinska EA,Kohl P,Khalimonchuk O,Schaffer JE,Abel ED.Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121,DRP1,and OPA1 that promote mitochondrial fission.Circ Res 2018;122(1):58-73.
33 Aroor AR,Sowers JR,Bender SB,Nistala R,Garro M,Mugerfeld I,Hayden MR,Johnson MS,Salam M,Whaley-Connell A,Demarco VG.Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats.Endocrinology 2013;154(7):2501-2513.
34 Stacchiotti A,Favero G,Giugno L,Golic I,Korac A,Rezzani R.Melatonin efficacy in obese leptin-deficient mice heart.Nutrients 2017;9(12):E1323.
35 Whitaker RM,Corum D,Beeson CC,Schnellmann RG.Mitochondrial biogenesis as a pharmacological target:a new approach to acute and chronic diseases.Annu Rev Pharmacol Toxicol 2016;56:229-249.
36 Zhang Y,Xu H.Translational regulation of mitochondrial biogenesis.Biochem Soc Trans 2016;44(6):1717-1724.
37 Ren J,Pulakat L,Whaley-Connell A,Sowers JR.Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease.J Mol Med(Berl)2010;88(10):993-1001.
38 Neves FA,Cortez E,Bernardo AF,Mattos AB,Vieira AK,Malafaia Tde O,Thole AA,Rodrigues-Cunha AC,Garcia-Souza EP,Sichieri R,Moura AS.Heart energy metabolism impairment in Western-diet induced obese mice.J Nutr Biochem 2014;25(1):50-57.
39 Xu M,Xue RQ,Lu Y,Yong SY,Wu Q,Cui YL,Zuo XT,Yu XJ,Zhao M,Zang WJ.Choline ameliorates cardiac hypertrophy by regulating metabolic remodelling and UPRmt through SIRT3-AMPK pathway.Cardiovasc Res 2019;115(3):530-545.
40 Kubli DA,Gustafsson AB.Mitochondria and mitophagy:the yin and yang of cell death control.Circ Res 2012;111(9):1208-1221.
41 Okatsu K,Oka T,Iguchi M,Imamura K,Kosako H,Tani N,Kimura M,Go E,Koyano F,Funayama M,Shiba-Fukushima K,Sato S,Shimizu H,Fukunaga Y,Taniguchi H,Komatsu M,Hattori N,Mihara K,Tanaka K,Matsuda N.PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria.Nat Commun 2012;3:1016.
42 Saito T,Sadoshima J.Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart.Circ Res 2015;116(8):1477-1490.
43 Wu W,Xu H,Wang Z,Mao Y,Yuan L,Luo W,Cui Z,Cui T,Wang XL,Shen YH.PINK1-parkin-mediated mitophagy protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury.PLoS One 2015;10(7):e0132499.
44 Montgomery MK,Turner N.Mitochondrial dysfunction and insulin resistance:an update.Endocr Connect 2015;4(1):R1-R15.
45 Brown DA,Perry JB,Allen ME,Sabbah HN,Stauffer BL,Shaikh SR,Cleland JG,Colucci WS,Butler J,Voors AA,Anker SD,Pitt B,Pieske B,Filippatos G,Greene SJ,Gheorghiade M.Expert consensus document:Mitochondrial function as a therapeutic target in heart failure.Nat Rev Cardiol2017;14(4):238-250.
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