A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis

BH Ahn, HS Kim, S Song, IH Lee… - Proceedings of the …, 2008 - National Acad Sciences
BH Ahn, HS Kim, S Song, IH Lee, J Liu, A Vassilopoulos, CX Deng, T Finkel
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
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 …
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.
National Acad Sciences