Abstract
Lysine acetylation is rapidly becoming established as a key post-translational modification for regulating mitochondrial metabolism. Nonetheless, distinguishing regulatory sites from among the thousands identified by mass spectrometry and elucidating how these modifications alter enzyme function remain primary challenges. Here, we performed multiplexed quantitative mass spectrometry to measure changes in the mouse liver mitochondrial acetylproteome in response to acute and chronic alterations in nutritional status, and integrated these data sets with our compendium of predicted Sirt3 targets. These analyses highlight a subset of mitochondrial proteins with dynamic acetylation sites, including acetyl-CoA acetyltransferase 1 (Acat1), an enzyme central to multiple metabolic pathways. We performed in vitro biochemistry and molecular modeling to demonstrate that acetylation of Acat1 decreases its activity by disrupting the binding of coenzyme A. Collectively, our data reveal an important new target of regulatory acetylation and provide a foundation for investigating the role of select mitochondrial protein acetylation sites in mediating acute and chronic metabolic transitions.
Highlights
Lysine acetylation, a prevalent post-translational modification, alters mitochondrial metabolism in response to nutrient changes
We hypothesize that the subset of mitochondrial protein acetylation sites with changing occupancy upon refeeding represent those most likely to have a regulatory function during this transition
Rat liver Mdh2 activity is increased upon feeding [35], and previous studies have reported that Mdh2 activity can be increased either by acetylation [36] or by Sirt3-dependent deacetylation [18]
Summary
A prevalent post-translational modification, alters mitochondrial metabolism in response to nutrient changes. We performed multiplexed quantitative mass spectrometry to measure changes in the mouse liver mitochondrial acetylproteome in response to acute and chronic alterations in nutritional status, and integrated these data sets with our compendium of predicted Sirt targets These analyses highlight a subset of mitochondrial proteins with dynamic acetylation sites, including acetyl-CoA acetyltransferase 1 (Acat1), an enzyme central to multiple metabolic pathways. To further prioritize mitochondrial lysine acetylation sites that are the most likely to be important for metabolic flexibility, we integrated these large-scale data sets with our compendium of predicted Sirt targets [18] Together, these analyses highlighted a select set of mitochondrial proteins as being likely targets for regulatory acetylation, including acetyl-CoA acetyltransferase 1 (Acat1), which possessed several sites of highly dynamic acetylation. Our work reveals Acat as an important new metabolic target of reversible acetylation and provides a resource of prioritized acetylation sites for future investigations into the role of this PTM in regulating mitochondrial protein function [19]
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