SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation

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Abstract
The sirtuin family of regulatory proteins has been implicated in various biological pathways including responses to calorie restriction and metabolic stress. Work in mice now shows that sirtuin 3 (SIRT3), which mediates deacetylation of several mitochondrial proteins, is induced in liver and brown adipose tissue during fasting. One of SIRT3's substrates is shown to be long-chain acyl co-enzyme A dehydrogenase (LCAD). Without SIRT3, LCAD becomes hyperacetylated, which diminishes its activity, and reduces fatty acid oxidation. Mice without SIRT3 have all the hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold. These findings suggest that acetylation is a novel regulatory mechanism for fatty acid oxidation. During fasting SIRT3 is induced in liver and brown adipose tissue. One of SIRT3's substrates is shown to be long–chain acyl co-enzyme A dehydrogenase (LCAD). Without SIRT3 LCAD becomes hyperacetylated, which diminishes its activity, and reduces fatty acid oxidation. Mice without SIRT3 have all the hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold. Thus, acetylation is a novel regulatory mechanism for fatty acid oxidation. Sirtuins are NAD+-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins3. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.