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https://hdl.handle.net/10316/110167
Title: | Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy | Authors: | Hafner, Angela V. Dai, Jing Gomes, Ana P. Xiao, Chun-Yang Palmeira, Carlos M. Rosenzweig, Anthony Sinclair, David A. |
Keywords: | sirtuin; mitochondria; acetylation; cardiac; mitochondrial permeability transition; mPTP; obesity; calorie restriction | Issue Date: | Dec-2010 | Publisher: | Impact Journals | Project: | Work was supported by NIH as R01 AG028730-01 and P01 AG027916 to D.S. D.S. is supported by the Glenn Foundation for Medical Research and a Senior Fellowship from the Ellison Medical Foundation Senior Scholar in Aging, A.R. gratefully acknowledges support from the NIH, a Leducq Foundation Network of Research Excellence, Judith and David Ganz, and the Maxwell Hurston Charitable Foundation. A.R. is a principal faculty member of the Harvard Stem Cell Institute | Serial title, monograph or event: | Aging | Volume: | 2 | Issue: | 12 | Abstract: | 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. | URI: | https://hdl.handle.net/10316/110167 | ISSN: | 1945-4589 | DOI: | 10.18632/aging.100252 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
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