SIRT3 Mediates Multi-Tissue Coupling for Metabolic Fuel Switching

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. [Display omitted] •Comprehensive, quantitative multi-tissue acetylome analysis•SIRT3 functions in both common and tissue-specific metabolic pathways•SIRT3 regulates ketone body utilization in extra-hepatic tissues•Pathway analysis tool incorporating site-specific acetylation dynamics Using multi-tissue quantitative acetyl-proteomics combined with bioinformatic analysis and biochemical validation, Dittenhafer-Reed et al. provide a comprehensive view of mitochondrial acetylation and SIRT3 function. SIRT3 coordinates metabolic homeostasis between fuel-producing (liver and kidney) and fuel-utilizing tissues (brain, heart, skeletal muscle) via dynamic acetylation, including ketone body utilization in the brain.