Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: Chemical and metabolic logic of acetyl-lysine modifications

Abstract

Hormone systems evolved over 500 million years of animal natural history to motivate feeding behavior and convert excess calories to fat. These systems produced vertebrates, including humans, who are famine-resistant but sensitive to obesity in environments of persistent overnutrition. We looked for cell-intrinsic metabolic features, which might have been subject to an evolutionary drive favoring lipogenesis. Mitochondrial protein acetylation appears to be such a system. Because mitochondrial acetyl-coA is the central mediator of fuel oxidation and is saturable, this metabolite is postulated to be the fundamental indicator of energy excess, which imprints a memory of nutritional imbalances by covalent modification. Fungal and invertebrate mitochondria have highly acetylated mitochondrial proteomes without an apparent mitochondrially targeted protein lysine acetyltransferase. Thus, mitochondrial acetylation is hypothesized to have evolved as a nonenzymatic phenomenon. Because the pK_a of a nonperturbed Lys is 10.4 and linkage of a carbonyl carbon to an ɛ amino group cannot be formed with a protonated Lys, we hypothesize that acetylation occurs on residues with depressed pK_a values, accounting for the propensity of acetylation to hit active sites and suggesting that regulatory Lys residues may have been under selective pressure to avoid or attract acetylation throughout animal evolution. In addition, a shortage of mitochondrial oxaloacetate under ketotic conditions can explain why macronutrient insufficiency also produces mitochondrial hyperacetylation. Reduced mitochondrial activity during times of overnutrition and undernutrition would improve fitness by virtue of resource conservation. Micronutrient insufficiency is predicted to exacerbate mitochondrial hyperacetylation. Nicotinamide riboside and Sirt3 activity are predicted to relieve mitochondrial inhibition.

• Ac-coA
• calorie restriction
• lipogenesis
• NAD⁺
• overnutrition
• oxaloacetate
• pK_a
• Sirt3

Acknowledgements

The authors thank members of the Brenner laboratory, reviewers, and multiple conferees at NAD Metabolism & Signaling and Evolution in Core Processes in Gene Regulation for encouragement and helpful discussions.

Declaration of interest

SG was supported by a Center for Biocatalysis and Bioprocessing training grant. REG was supported by K01GM109309 from the National Institutes of Health. Work on reversible acetylation in the CB laboratory was supported by the National Science Foundation and the Roy J. Carver Trust. The authors report no conflicts of interest.