SIRT3 Regulates Mitochondrial Protein Acetylation and Intermediary Metabolism

The sirtuins are a family of nicotinamide adenine dinucleotide (NAD þ )-dependent protein deacetylases that regulate cell survival, metabolism, and longevity.Humans have seven sirtuins (SIRT1-SIRT7) with distinct subcellular locations and functions.SIRT3 is localized to the mitochondrial matrix and its expression is selectively activated during fasting and calorie restriction.Activated SIRT3 deacetylates several key metabolic enzymes-acetyl-coenzyme A synthetase, long-chain acylcoenzyme A (acyl-CoA) dehydrogenase (LCAD), and 3-hydroxy-3-methylglutaryl CoA synthase 2-and enhances their enzymatic activity.Disruption of SIRT3 activity in mice, either by genetic ablation or during high-fat feeding, is associated with accelerated development of metabolic abnormalities similar to the metabolic syndrome in humans.SIRT3 is therefore emerging as a metabolic sensor that responds to change in the energy status of the cell and modulates the activity of key metabolic enzymes via protein deacetylation.