A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis

Bong Hyun Ahn, Hyun Seok Kim, Shiwei Song, Hye Lee In, Jie Liu, Athanassios Vassilopoulos, Chu Xia Deng*, Toren Finkel

*Corresponding author for this work

Research output: Contribution to journalArticle

788 Scopus citations

Abstract

Here, we demonstrate a role for the mitochondrial NAD-dependent deacetylase Sirt3 in the maintenance of basal ATP levels and as a regulator of mitochondrial electron transport. We note that Sirt3-/- mouse embryonic fibroblasts have a reduction in basal ATP levels. Reconstitution with wild-type but not a deacetylase-deficient form of Sirt3 restored ATP levels in these cells. Furthermore in wild-type mice, the resting level of ATP correlates with organ-specific Sirt3 protein expression. Remarkably, in mice lacking Sirt3, basal levels of ATP in the heart, kidney, and liver were reduced >50%. We further demonstrate that mitochondrial protein acetylation is markedly elevated in Sirt3-/- tissues. In addition, in the absence of Sirt3, multiple components of Complex I of the electron transport chain demonstrate increased acetylation. Sirt3 can also physically interact with at least one of the known subunits of Complex I, the 39-kDa protein NDUFA9. Functional studies demonstrate that mitochondria from Sirt3-/- animals display a selective inhibition of Complex I activity. Furthermore, incubation of exogenous Sirt3 with mitochondria can augment Complex I activity. These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels.

Original languageEnglish (US)
Pages (from-to)14447-14452
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number38
DOIs
StatePublished - Sep 23 2008

Keywords

  • Acetylation
  • Complex
  • Electron transport
  • Sirtuins

ASJC Scopus subject areas

  • General

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