Mitochondrial Sirtuin Network Reveals Dynamic SIRT3-dependent Deacetylation in Response to Membrane Depolarization
Yang Wen1, Seungmin Jeong1, Koji Nagasawa1,2, Sebastian D Hayes1, Christian Munch1, Mark P. Jedrychowski1, Virginia Guarani1,F. Kyle Satterstrom1, Sejal Kamlesh Vyas1; Yingjie Xu3, Steven P. Gygi1, J. Wade Harper1, and Marcia C Haigis1* 1Department of CellBiology, Harvard Medical School, Boston, MA, USA, 02115 2Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan 3Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, 02115 *Corresponding author: firstname.lastname@example.org
The mitochondrial sirtuins, SIRT3-5, maintain energy homeostasis during nutrient and cellular stress, and their dysfunction has been implicated in human diseases, ranging from diabetes to cancer. We employ systematic proteomics to describe the mitochondrial sirtuin interaction landscape. Mitochondrial sirtuins display both overlapping and unique interaction partners. SIRT3 presents the most extensive and most diverse collection of binding targets, linking this key enzyme to energy metabolism, protein turnover, and nucleic acid biology. Furthermore, our studies uncovered a new mechanism by which SIRT3 is regulated in response to mitochondrial stress. We found that SIRT3 forms a unique association with Complex V that is destabilized with low mitochondrial membrane potential. Moreover, a decrease of mitochondrial membrane potential changes the topology of the SIRT3 interactome. We further revealed this regulation of SIRT3 plays a role in maintaining mitochondrial energy homeostasis.
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