Abstract
Alterations in mitochondrial protein acetylation are implicated in the pathophysiology of diabetes, the metabolic syndrome, mitochondrial disorders, and cancer. However, a viable mechanism responsible for the widespread acetylation in mitochondria remains unknown. Here, we demonstrate that the physiologic pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to cause dose- and time-dependent, but enzyme-independent acetylation and succinylation of mitochondrial and nonmitochondrial proteins in vitro. These data suggest that protein acylation in mitochondria may be a chemical event facilitated by the alkaline pH and high concentrations of reactive acyl-CoAs present in the mitochondrial matrix. Although these results do not exclude the possibility of enzyme-mediated protein acylation in mitochondria, they demonstrate that such a mechanism may not be required in its unique chemical environment. These findings may have implications for the evolutionary roles that the mitochondria-localized SIRT3 deacetylase and SIRT5 desuccinylase have in the maintenance of metabolic health.
Highlights
The mechanisms initiating protein acylation in mitochondria are unknown
We demonstrate that the minimal chemical conditions of the mitochondrial matrix are sufficient to cause nonenzymatic protein lysine acetylation. We broaden these findings by demonstrating that this distinct chemical environment promotes nonenzymatic protein succinylation by succinyl-CoA, suggesting that this post-translational mechanism may extend to several short-chain acyl-CoA intermediates present within mitochondria. This is the first study to systematically demonstrate that the chemical conditions of the mitochondrial matrix are sufficient to cause nonenzymatic acylation of proteins, which provides a viable mechanism for the pervasive protein acylation in this organelle and, perhaps, an evolutionary basis for the mitochondrialocalized SIRT3 deacetylase and SIRT5 desuccinylase
Incubating nonacetylated BSA with 0.5 mM succinyl-CoA caused a pH-dependent increase in lysine succinylation (Fig. 4C). This is the first study reporting nonenzymatic protein succinylation by succinyl-CoA at physiological pH. These results demonstrated that the pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to induce widespread and enzyme-independent protein lysine acylation
Summary
The mechanisms initiating protein acylation in mitochondria are unknown. Results: The pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to cause protein lysine acetylation and succinylation. We demonstrate that the minimal chemical conditions of the mitochondrial matrix are sufficient to cause nonenzymatic protein lysine acetylation We broaden these findings by demonstrating that this distinct chemical environment promotes nonenzymatic protein succinylation by succinyl-CoA, suggesting that this post-translational mechanism may extend to several short-chain acyl-CoA intermediates present within mitochondria. To our knowledge, this is the first study to systematically demonstrate that the chemical conditions of the mitochondrial matrix are sufficient to cause nonenzymatic acylation of proteins, which provides a viable mechanism for the pervasive protein acylation in this organelle and, perhaps, an evolutionary basis for the mitochondrialocalized SIRT3 deacetylase and SIRT5 desuccinylase
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