Widespread and enzyme-independent Nε-acetylation and Nε-succinylation of proteins in the chemical conditions of the mitochondrial matrix.
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.
From the Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202 and.
Gregory R
GR
Wagner
R Mark
RM
Payne
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D003065:Coenzyme A / Q000378:metabolism; D019295:Computational Biology; D006863:Hydrogen-Ion Concentration; D006878:Hydroxides / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D056566:Sirtuin 3 / Q000378:metabolism; D013386:Succinates / Q000378:metabolism*
D006878:Hydroxides; D024101:Mitochondrial Proteins; D013386:Succinates; C031356:hydroxide ion; D056566:Sirtuin 3; D003065:Coenzyme A
Acetyl Coenzyme A; Acetylation; Metabolic Diseases; Metabolic Regulation; Mitochondrial Metabolism; Nonenzymatic; Sirtuins; Succinyl Coenzyme A; Succinylation; pH Regulation