Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy

被引:430
作者
Hafner, Angela V. [1 ,2 ,3 ]
Dai, Jing [5 ]
Gomes, Ana P. [1 ,2 ,4 ]
Xiao, Chun-Yang [5 ]
Palmeira, K. Carlos M. [4 ]
Rosenzweig, Anthony [5 ]
Sinclair, David A. [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Glenn Labs Aging Res, Boston, MA 02115 USA
[3] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany
[4] Univ Coimbra, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal
[5] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc,Ctr Life Sci, Boston, MA 02115 USA
来源
AGING-US | 2010年 / 2卷 / 12期
关键词
sirtuin; mitochondria; acetylation; cardiac; mitochondrial permeability transition; mPTP; obesity; calorie restriction; MITOCHONDRIAL PERMEABILITY TRANSITION; CYCLOPHILIN-D; HEART-MITOCHONDRIA; CELL-DEATH; SIRTUINS; SIRT3; PORE; RESTRICTION; ACETYLATION; DISEASE;
D O I
10.18632/aging.100252
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Cardiac failure is a leading cause of age-related death, though its root cause remains unknown. Mounting evidence implicates a decline in mitochondrial function due to increased opening of the mitochondrial permeability transition pore (mPTP). Here we report that the NAD+-dependent deacetylase SIRT3 deacetylates the regulatory component of the mPTP, cyclophilin D (CypD) on lysine 166, adjacent to the binding site of cyclosporine A, a CypD inhibitor. Cardiac myocytes from mice lacking SIRT3 exhibit an age-dependent increase in mitochondrial swelling due to increased mPTP opening, a phenotype that is rescued by cyclosporine A. SIRT3 knockout mice show accelerated signs of aging in the heart including cardiac hypertrophy and fibrosis at 13 months of age. SIRT3 knockout mice are also hypersensitive to heart stress induced by transverse aortic constriction (TAC), as evidenced by cardiac hypertrophy, fibrosis, and increased mortality. Together, these data show for the first time that SIRT3 activity is necessary to prevent mitochondrial dysfunction and cardiac hypertrophy during aging and shed light on new pharmacological approaches to delaying aging and treating diseases in cardiac muscle and possibly other post-mitotic tissues.
引用
收藏
页码:914 / 923
页数:10
相关论文
共 39 条
[1]   Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death [J].
Baines, CP ;
Kaiser, RA ;
Purcell, NH ;
Blair, NS ;
Osinska, H ;
Hambleton, MA ;
Brunskill, EW ;
Sayen, MR ;
Gottlieb, RA ;
Dorn, GW ;
Robbins, J ;
Molkentin, JD .
NATURE, 2005, 434 (7033) :658-662
[2]  
DAI H, 2010, J BIOL CHEM
[3]   Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart [J].
Di Lisa, F ;
Menabò, R ;
Canton, M ;
Barile, M ;
Bernardi, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (04) :2571-2575
[4]   Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease [J].
Du, Heng ;
Guo, Lan ;
Fang, Fang ;
Chen, Doris ;
Sosunov, Alexander A. ;
McKhann, Guy M. ;
Yan, Yilin ;
Wang, Chunyu ;
Zhang, Hong ;
Molkentin, Jeffery D. ;
Gunn-Moore, Frank J. ;
Vonsattel, Jean Paul ;
Arancio, Ottavio ;
Chen, John Xi ;
Du Yan, Shi .
NATURE MEDICINE, 2008, 14 (10) :1097-1105
[5]   Mitochondrial permeability transition pore in Alzheimer's disease: Cyclophilin D and amyloid beta [J].
Du, Heng ;
Yan, Shirley ShiDu .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2010, 1802 (01) :198-204
[6]   Cyclophilin D controls mitochondrial pore-dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice [J].
Elrod, John W. ;
Wong, Renee ;
Mishra, Shikha ;
Vagnozzi, Ronald J. ;
Sakthievel, Bhuvana ;
Goonasekera, Sanjeewa A. ;
Karch, Jason ;
Gabel, Scott ;
Farber, John ;
Force, Thomas ;
Brown, Joan Heller ;
Murphy, Elizabeth ;
Molkentin, Jeffery D. .
JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (10) :3680-3687
[7]   Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis [J].
Forte, Michael ;
Gold, Bruce G. ;
Marracci, Gail ;
Chaudhary, Priya ;
Basso, Emy ;
Johnsen, Dustin ;
Yu, Xiaolin ;
Fowlkes, Jonathan ;
Bernardi, Paolo ;
Bourdette, Dennis .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (18) :7558-7563
[8]   Mitochondria - A nexus for aging, calorie restriction, and sirtuins? [J].
Guarente, Leonard .
CELL, 2008, 132 (02) :171-176
[9]   Mammalian Sirtuins: Biological Insights and Disease Relevance [J].
Haigis, Marcia C. ;
Sinclair, David A. .
ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE, 2010, 5 :253-295
[10]   Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases [J].
Hallows, William C. ;
Lee, Susan ;
Denu, John M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (27) :10230-10235