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Cell Metab. 2014 Nov 4;20(5):856-69. doi: 10.1016/j.cmet.2014.08.001. Epub 2014 Sep 4.

A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function.

Author information

1
Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
2
Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
3
Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
4
Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 137-701, Republic of Korea.
5
Unit of Molecular Neurogenetics, the Carlo Besta Institute of Neurology IRCCS, 20133 Milan, Italy; MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, UK.
6
Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, France.
7
Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.
8
Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.

Abstract

Mitochondrial activity is controlled by proteins encoded by both nuclear and mitochondrial DNA. Here, we identify Sirt7 as a crucial regulator of mitochondrial homeostasis. Sirt7 deficiency in mice induces multisystemic mitochondrial dysfunction, which is reflected by increased blood lactate levels, reduced exercise performance, cardiac dysfunction, hepatic microvesicular steatosis, and age-related hearing loss. This link between SIRT7 and mitochondrial function is translatable in humans, where SIRT7 overexpression rescues the mitochondrial functional defect in fibroblasts with a mutation in NDUFSI. These wide-ranging effects of SIRT7 on mitochondrial homeostasis are the consequence of the deacetylation of distinct lysine residues located in the hetero- and homodimerization domains of GABPβ1, a master regulator of nuclear-encoded mitochondrial genes. SIRT7-mediated deacetylation of GABPβ1 facilitates complex formation with GABPα and the transcriptional activation of the GABPα/GABPβ heterotetramer. Altogether, these data suggest that SIRT7 is a dynamic nuclear regulator of mitochondrial function through its impact on GABPβ1 function.

PMID:
25200183
DOI:
10.1016/j.cmet.2014.08.001
[Indexed for MEDLINE]
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