The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications

Abstract

Post-translational modification of lysine residues via reversible acylation occurs on proteins from diverse pathways, functions, and organisms. While nuclear protein acylation reflects the competing activities of enzymatic acyltransferases and deacylases, mitochondrial acylation appears to be driven mostly via a non-enzymatic mechanism. Three protein deacylases, SIRT3, SIRT4, and SIRT5, reside in the mitochondria and remove these modifications from targeted proteins in an NAD-dependent manner. Recent proteomic surveys of mitochondrial protein acylation have identified the sites of protein acetylation, succinylation, glutarylation, and malonylation and their regulation by SIRT3 and SIRT5. Here, we review recent advances in this rapidly moving field, their biological significance, and their implications for mitochondrial function, metabolic regulation, and disease pathogenesis.

Proteomics of Long‐Lived Mammals

“…Metabolic disorder (as obesity or in type II diabetes) and CR regimens confer opposing effects on aging and affect the levels of PTMs such as acylations of mitochondrial proteins or ubiquitination . Many of the changes that occur in metabolic disorder occur naturally during aging are accelerated by the disorder and alleviated by CR.…”

“…Expanding this concept to other proteins would be a long‐term goal. One example of this is the novel role of sirtuins such as SIRT3, 4, and 5 in regulating mitochondrial protein acylations . A second area that would permit an understanding of biological context is to reveal crosstalk between PTM sites.…”

Protein Acetylation Induced by Dichloroacetate (DCA) Treatment is Associated with Decreased Respiration in Cultured Hepatocytes: Preliminary Results

“…All these conditions must increase the equilibrium level of acetylation by either altering the production of acetyl-CoA or altering the rate of lysine acetylation removal. Protein acylation is removed by deacetylases, which include the NAD+-dependent class of deacetylates named Sirtuins 17 . Considerable effort has been devoted to the study of Sirtuin proteins since the discovery that their activity is positively correlated with lifespan 18,19 .…”

P300/CBP‐associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

“…Interestingly, injured mitochondria represent a risk factor contributing to apoptosis and to the onset of neurologic disorders or myopathies (13)(14)(15). Of note, a large number of mitochondrial proteins are acetylated at lysine residues, and this post-translational modification (PTM) seems the most prevalent protein modification occurring in this subcellular compartment with important functional consequences for those enzymes segregated therein (16).…”

“…Recently, different acetyl-proteomic approaches, aimed at the identification of the whole-cell acetylome, revealed a broad distribution of acetylation, particularly enriched in metabolic and mitochondrial proteins, although only few of them have been, at present, independently validated (16)(17)(18). Nonenzymatic acetylation is commonly ascribed as the most important mechanism of acetylation active in mitochondria (16), as a consequence of the high pH level and acetyl-coenzyme A (acetyl-CoA) concentration present in this specific subcellular compartment, which might favor a spontaneous and nonspecific, low stoichiometry reaction (19). This widespread acetylation is counteracted by the enzymatic activity of sirtuin 3 (SIRT3), a class III histone deacetylase belonging to the sirtuin family localized into the mitochondrial matrix (20,21).…”