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Sirtuin 3 is a Novel Regulator of Mitochondrial Ceramide Metabolism in Stroke
Author(s) -
Gudz Tatyana I.,
Riley Christopher,
Keffler Jarryd,
Yu Jin,
Kindy Mark,
Macklin Wendy,
Lombard David,
Novgorodov Sergei
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1133.1
Subject(s) - sirt3 , ceramide , ceramide synthase , mitochondrion , acetylation , sphingolipid , microbiology and biotechnology , sirtuin , lipid signaling , chemistry , nad+ kinase , biology , biochemistry , enzyme , gene , apoptosis
Experimental evidence supports the role of mitochondrial ceramide accumulation as a cause of mitochondrial dysfunction and brain injury after stroke. Herein, we report that SIRT3 regulates mitochondrial ceramide biosynthesis via deacetylation of ceramide synthase (CerS) 1, 2 and 6. Reciprocal immunoprecipitation experiments revealed that CerS1, CerS2 and CerS6, but not CerS4, are associated with SIRT3 in cerebral mitochondria. Furthermore, CerS1, 2 and 6 are hyper‐acetylated in the mitochondria of SIRT3‐null mice and SIRT3 directly deacetylates the ceramide synthases in a NAD + ‐dependent manner that increases enzyme activity. Investigation of SIRT3 role in mitochondrial response to brain ischemia/reperfusion (IR) showed that SIRT3‐mediated deacetylation of ceramide synthases increased enzyme activity and ceramide accumulation after IR. Functional studies demonstrated that absence of SIRT3 rescued the IR‐induced blockade of the electron‐transport chain at the level of Complex III, decreased ROS generation and protein carbonyls in mitochondria. Importantly, Sirt3 gene ablation protected the brain from IR injury. These data support the hypothesis that IR activates SIRT3, resulting in the deacetylation of ceramide synthases and the elevation of ceramide which could inhibit Complex III, leading to increased ROS generation and brain injury. The results of these studies highlight a novel mechanism of SIRT3 involvement in modulating mitochondrial ceramide biosynthesis and suggest a critical role of SIRT3 in promoting mitochondrial dysfunction and brain injury after stroke. Support or Funding Information NIH grant NS083544