title: SDHAF4 promotes mitochondrial succinate dehydrogenase activity and prevents neurodegeneration.
abstract: Succinate dehydrogenase (SDH) occupies a central place in cellular energy production, linking the tricarboxylic cycle with the electron transport chain. As a result, a subset of cancers and neuromuscular disorders result from mutations affecting any of the four SDH structural subunits or either of two known SDH assembly factors. Herein we characterize an evolutionarily conserved SDH assembly factor designated Sdh8/SDHAF4, using yeast, Drosophila, and mammalian cells. Sdh8 interacts specifically with the catalytic Sdh1 subunit in the mitochondrial matrix, facilitating its association with Sdh2 and the subsequent assembly of the SDH holocomplex. These roles for Sdh8 are critical for preventing motility defects and neurodegeneration in Drosophila as well as the excess ROS generated by free Sdh1. These studies provide insights into the mechanisms by which SDH is assembled and raise the possibility that some forms of neuromuscular disease may be associated with mutations that affect this SDH assembly factor.
authors: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Jonathan G
authors: JG
authors: Van Vranken
authors: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Daniel K
authors: DK
authors: Bricker
authors: Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA.
authors: Noah
authors: N
authors: Dephoure
authors: Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA.
authors: Steven P
authors: SP
authors: Gygi
authors: Metabolomics Core Research Facility, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: James E
authors: JE
authors: Cox
authors: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: carl.thummel@genetics.utah.edu.
authors: Carl S
authors: CS
authors: Thummel
authors: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: rutter@biochem.utah.edu.
authors: Jared
authors: J
authors: Rutter
mesh_terms: D000818:Animals; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C528541:SDH1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase