Chemical and Physiological Features of Mitochondrial Acylation

Abstract

Growing appreciation of the diversity of post-translational modifications (PTMs) in the mitochondria necessitates reevaluation of the roles these modifications play in both health and disease. Compared to the cytosol and nucleus, the mitochondrial proteome is highly acylated, and remodeling of the mitochondrial "acylome" is a key adaptive mechanism that regulates fundamental aspects of mitochondrial biology. It is clear that we need to understand the underlying chemistry that regulates mitochondrial acylation, as well as how chemical properties of the acyl chain impact biological functions. Here, we dissect the sources of PTMs in the mitochondria, review major mitochondrial pathways that control levels of PTMs, and highlight how sirtuin enzymes respond to the bioenergetic state of the cell via NAD⁺ availability to regulate mitochondrial biology. By providing a framework connecting the chemistry of these modifications, their biochemical consequences, and the pathways that regulate the levels of acyl PTMs, we will gain a deeper understanding of the physiological significance of mitochondrial acylation and its role in mitochondrial adaptation.

Figure 1.

Lysine acyl modifications possess diverse chemical properties. (A) Table summarizing the chemical properties (structure, charge, hydrophobicility) and metabolic sources of lysine acyl PTMs. (B) The hydrophobicity of lysine acyl PTMs based on pH-adjusted water octanol partitioning coefficient varies widely. Abbreviations: FAO – fatty acid oxidation. BCAA – branched chain amino acid. MCD – malonyl-CoA decarboxylase.

Figure 2.

Overview of mitochondrial roles for sirtuins in metabolism. (A) Sirtuins remove lysine PTMs from enzymes that produce, consume, or interconvert mitochondrial acyl-CoA pools. Green arrows denote deacylation activities that enhance the catalytic activity of the substrate. Red bars highlight deacylation activities that inhibit substrate activity. Abbreviations: ACAT1 – Acetyl-CoA Acetyltransferase 1, AceCS2 – Acetyl-CoA Synthetase 2, BCAA – Branched chain amino acids, CPT1A – Carnitine Palmitoyltransferase 1A, GDH – Glutamate Dehydrogenase, HmgCS2 – 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2, LCAD – Long Chain Acyl-CoA Dehydrogenase, MCCC – Methylcrotonyl-CoA Carboxylase, MCD – Malonyl-CoA decarboxylase, MPC1 – Mitochondrial Pyruvate Carrier 1, PDH – Pyruvate Dehydrogenase, SDH – Succinate Dehydrogenase, VLCAD – Very Long Chain Acyl-CoA Dehydrogenase. (B) Overview of metabolic pathways regulation by mitochondrial sirtuins.

Figure 3.

Mechanisms connecting the physical properties of lysine acyl PTMs to changes in macromolecular function.

Figure 4.

The activity of mitochondrial sirtuins connects fluctuations in NAD+ metabolism to changes in protein acylation. Abbreviations: Ac – Acetate, ADPr – ADPribose, AMP – adenosine monophosphate, NAD⁺ – Nicotinamide Adenine Dinucleotide, NADH – Nicotinamide Adenine Dinucleotide Hydride, NA – Nicotinic Acid, NaAD – Nicotinic Acid Adenine Dinucleotide, NAM – Nicotinamide, NaMN – Nicotinic Acid Mononucleotide, NMN – Nicotinamide Mononucleotide, NR – Nicotinamide Riboside, OAcADPr – O-Acetyl-ADPribose, OAADPr – O-Acyl-ADPribose.