title: SIRT3 mediates multi-tissue coupling for metabolic fuel switching.
abstract: 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.
authors: Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Kristin E
authors: KE
authors: Dittenhafer-Reed
authors: Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA; The Genome Center of Wisconsin, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Alicia L
authors: AL
authors: Richards
authors: Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Jing
authors: J
authors: Fan
authors: Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Michael J
authors: MJ
authors: Smallegan
authors: Department of Computer Sciences, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Alireza
authors: A
authors: Fotuhi Siahpirani
authors: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Zachary A
authors: ZA
authors: Kemmerer
authors: Department of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Tomas A
authors: TA
authors: Prolla
authors: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Sushmita
authors: S
authors: Roy
authors: Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA; Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA; The Genome Center of Wisconsin, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors: Joshua J
authors: JJ
authors: Coon
authors: Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA. Electronic address: jmdenu@wisc.edu.
authors: John M
authors: JM
authors: Denu
mesh_terms: D000107:Acetylation; D000818:Animals; D001921:Brain / Q000378:metabolism; D019295:Computational Biology; D005786:Gene Expression Regulation / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D040901:Proteomics; D056566:Sirtuin 3 / Q000378:metabolism*
chemical_list: D007657:Ketone Bodies; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3