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Cell Metab. 2015 Apr 7;21(4):637-46. doi: 10.1016/j.cmet.2015.03.007.

SIRT3 mediates multi-tissue coupling for metabolic fuel switching.

Author information

1
Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
2
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA; The Genome Center of Wisconsin, University of Wisconsin, Madison, Wisconsin 53715, USA.
3
Department of Computer Sciences, University of Wisconsin, Madison, Wisconsin 53715, USA.
4
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
5
Department of Genetics and Medical Genetics, University of Wisconsin, Madison, Wisconsin 53715, USA.
6
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53715, USA.
7
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.
8
Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA. Electronic address: jmdenu@wisc.edu.

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.

PMID:
25863253
PMCID:
PMC4393847
DOI:
10.1016/j.cmet.2015.03.007
[Indexed for MEDLINE]
Free PMC Article

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