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.
Ahn
Bong-Hyun
BH
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kim
Hyun-Seok
HS
Song
Shiwei
S
Lee
In Hye
IH
Liu
Jie
J
Vassilopoulos
Athanassios
A
Deng
Chu-Xia
CX
Finkel
Toren
T
D000107:Acetylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D056566:Sirtuin 3; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D024101:Mitochondrial Proteins; C525046:Sirt3 protein, mouse; D000255:Adenosine Triphosphate; D056566:Sirtuin 3; D037761:Sirtuins; D042967:Electron Transport Complex I
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