Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease

Abstract

The sirtuins are a family of NAD(+)-dependent protein deacetylases that regulate cell survival, metabolism, and longevity. Three sirtuins, SIRT3-5, localize to mitochondria. Expression of SIRT3 is selectively activated during fasting and calorie restriction. SIRT3 regulates the acetylation level and enzymatic activity of key metabolic enzymes, such as acetyl-CoA synthetase, long-chain acyl-CoA dehydrogenase, and 3-hydroxy-3-methylglutaryl-CoA synthase 2, and enhances fat metabolism during fasting. SIRT5 exhibits demalonylase/desuccinylase activity, and lysine succinylation and malonylation are abundant mitochondrial protein modifications. No convincing enzymatic activity has been reported for SIRT4. Here, we review the emerging role of mitochondrial sirtuins as metabolic sensors that respond to changes in the energy status of the cell and modulate the activities of key metabolic enzymes via protein deacylation.

FIGURE 1.

Mitochondrial acetyl-CoA, malonyl-CoA, and succinyl-CoA metabolism. Metabolic pathways resulting from the oxidation of glucose, fatty acids, and amino acids and leading to the synthesis of acetyl-CoA, malonyl-CoA, and succinyl-CoA are shown. Also shown are the two mechanisms leading to export of acetyl-CoA from mitochondria: ATP citrate lyase (CrAT) and carnitine/acylcarnitine translocase (CACT). BCAA, branched-chain amino acid; PK, pyruvate kinase; PEP, phosphoenolpyruvate; PEPCK, phosphoenolpyruvate carboxykinase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PCC, propionyl-CoA carboxylase; LCAD, long-chain acyl-CoA dehydrogenase; BCAT, branched-chain aminotransferase; BCKD, branched-chain α-keto acid dehydrogenase; MCM, methylmalonyl-CoA mutase; CPT, carnitine palmitoyltransferase.