A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis

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.