Reversible protein acetylation is a major regulatory mechanism for controlling protein function. Through genetic manipulations, dietary perturbations, and new proteomic technologies, the diverse functions of protein acetylation are coming into focus. Protein acetylation in mitochondria has taken center stage, revealing that 63% of mitochondrially localized proteins contain lysine acetylation sites. Here we summarize the field, and discuss salient topics that cover spurious versus targeted acetylation, the role of SIRT3 deacetylation, nonenzymatic acetylation, and molecular models for regulatory acetylations that display high and low stoichiometry.
Background: Lysine acetylation sites have been mapped, but information on stoichiometry is lagging. Results: We developed and utilized the first direct, unbiased method for quantifying site-specific acetylation stoichiometry of a proteome without antibody enrichment. Conclusion: High stoichiometry is associated with central metabolism, transcription, and translation. Loss of deacetylase CobB affects site-specific and global acetylation stoichiometry, altering acetyl-CoA metabolism. Significance: Stoichiometry provides functional insight into protein acetylation.
Summary
SIRT3 is a member of the Sirtuin family of NAD+-dependent deacylases and plays a critical role in metabolic regulation. Organism-wide SIRT3 loss manifests in metabolic alterations, however the coordinating role of SIRT3 among metabolically distinct tissues is unknown. Using multi-tissue quantitative proteomics comparing fasted wild type mice to mice lacking SIRT3, innovative bioinformatic analysis, and biochemical validation, we provide a comprehensive view of mitochondrial acetylation and SIRT3 function. We find SIRT3 regulates the acetyl-proteome in core mitochondrial processes common to brain, heart, kidney, liver, and skeletal muscle, but differentially regulates metabolic pathways in fuel-producing and fuel-utilizing tissues. We propose an additional maintenance function for SIRT3 in liver and kidney where SIRT3 expression is elevated to reduce the acetate load on mitochondrial proteins. We provide evidence that SIRT3 impacts ketone body utilization in the brain and reveal a pivotal role for SIRT3 in the coordination between tissues required for metabolic homeostasis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.