Reactive Acyl-CoA Species and Deacylation by the Mitochondrial Sirtuins

Abstract The sirtuins are a family of nicotinamide adenine dinucleotide (NAD + )-dependent enzymes that remove acyl-lysine modifications from a variety of proteins, thereby controlling a myriad of cellular processes. In mitochondria, reactive acyl-CoA species lead to a wide range of protein posttranslational modifications. Three sirtuins (SIRT3, SIRT4, and SIRT5) primarily localized in mitochondria remove distinct acyl-groups from lysine side chains, which control protein function. Indeed, high-resolution mass spectrometry-based proteomic studies have identified thousands of acyl-protein modifications across hundreds of mitochondrial proteins. Emerging evidence shows a relationship between physiological stress, changes in carbon metabolism and protein modifications, and a key role for sirtuins in maintaining metabolic homeostasis. In this chapter, we discuss key roles of the mitochondrial sirtuins, with a particular emphasis on cardiac studies. We also highlight key questions remaining in the field, including the mechanisms by which acylation influences protein function and the role of sirtuins in shaping the global mitochondrial acyl-lysine landscape.