SIRT3 Mediates Multi-Tissue Coupling for Metabolic Fuel Switching

Abstract

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.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

“…Because no tools directly assess SIRT3 activity in vivo, we assessed the acetylation status of cardiac SIRT3 targets as a surrogate for SIRT3 activity. First, we used a previously published multitissue acetyl-proteomic profiling of SIRT3-KO mice as a resource for identifying strong cardiac candidates of regulation by SIRT3 deacetylase activity (28). While both SIRT3-KO and FXN-KO datasets use comparable proteomic technology (isobaric tag-based quantitative proteomics with HCD fragmentation and Orbitrap mass analysis), subtle differences in sample processing and mass spectrometric analyses likely influence slight variation in dynamic range compression (i.e., measured fold change range) (29).…”

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

“…Lanza et al found that SIRT3 expression is downregulated with age, especially pronounced after 60 years old, and chronic endurance training causes elevation of SIRT3 expression along with beneficial health effects and potential lifespan-extending properties [74]. SIRT3, whose expression is rich in the heart, is the main deacetylase in the mitochondria and its absence produces hyperacetylation of numerous proteins in this organelle [75]. Increased acetylation of mitochondrial proteins, such as cyclophilin D, an important regulator of the permeability transition pore (mPTP), in the heart in response to IR injury has been reported [69,76].…”

Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1)

“…Sirtuins are a highly conserved family of proteins capable of catalyzing NAD ϩ -dependent deacylation and mono-(ADP-ribosyl)ation reactions (11). Sirtuin activation has been shown to modulate mitochondrial biogenesis and all major mitochondrial processes, including the tricarboxylic acid cycle, fatty acid metabolism, oxidative phosphorylation, and antioxidant response (4,(12)(13)(14)(15). Because all of the above NAD ϩ -consuming enzymes generate nicotinamide (NAM) as a byproduct, mammalian cells have evolved an NAD ϩ salvage pathway capable of resynthesizing NAD ϩ from NAM (16).…”