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

Aging (Albany NY). 2010 Dec;2(12):914-23. doi: 10.18632/aging.100252.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Age Factors
  • Aging*
  • Amino Acid Sequence
  • Animals
  • Cardiomegaly / enzymology
  • Cardiomegaly / genetics
  • Cardiomegaly / pathology
  • Cardiomegaly / prevention & control*
  • Cyclophilin D
  • Cyclophilins / chemistry
  • Cyclophilins / genetics
  • Cyclophilins / metabolism*
  • Cyclosporine / pharmacology
  • Disease Models, Animal
  • Humans
  • Lysine
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / enzymology*
  • Mitochondria, Heart / pathology
  • Mitochondrial Membrane Transport Proteins / chemistry
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Swelling
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Protein Conformation
  • Sirtuin 3 / deficiency
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism*
  • Structure-Activity Relationship
  • Time Factors

Substances

  • Cyclophilin D
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • PPIF protein, mouse
  • Sirt3 protein, mouse
  • Cyclosporine
  • Sirtuin 3
  • Cyclophilins
  • PPID protein, human
  • Lysine