@article{c95ce5e937934840adf273b82e7a17b4,
title = "IDH2-mediated regulation of the biogenesis of the oxidative phosphorylation system",
abstract = "Several subunits in the matrix domain of mitochondrial complex I (CI) have been posited to be redox sensors for CI, but how elevated levels of reactive oxygen species (ROS) impinge on CI assembly is unknown. We report that genetic disruption of the mitochondrial NADPH-generating enzyme, isocitrate dehydrogenase 2 (IDH2), in Drosophila flight muscles results in elevated ROS levels and impairment of assembly of the oxidative phosphorylation system (OXPHOS). Mechanistically, this begins with an inhibition of biosynthesis of the matrix domain of CI and progresses to involve multiple OXPHOS complexes. Despite activation of multiple compensatory mechanisms, including enhanced coenzyme Q biosynthesis and the mitochondrial unfolded protein response, ferroptotic cell death ensues. Disruption of enzymes that eliminate hydrogen peroxide, but not those that eliminate the superoxide radical, recapitulates the phenotype, thereby implicating hydrogen peroxide as the signaling molecule involved. Thus, IDH2 modulates the assembly of the matrix domain of CI and ultimately that of the entire OXPHOS.",
author = "Anjaneyulu Murari and Goparaju, {Naga S.V.} and Rhooms, {Shauna Kay} and Hossain, {Kaniz F.B.} and Liang, {Felix G.} and Garcia, {Christian J.} and Cindy Osei and Tong Liu and Hong Li and Kitsis, {Richard N.} and Rajesh Patel and Edward Owusu-Ansah",
note = "Funding Information: We thank past and present members of the Owusu-Ansah laboratory for general discussions. We also thank H. Colecraft, J. D{\textquoteright}Armiento, A. Galkin, W. Grueber, L. Johnston, A. Marks, M. Picard, M. Schlame, E. Schon, and M. Shirasu-Hiza for fly stocks, reagents, and critical discussions. We acknowledge the Bloomington Drosophila Stock Center and the Vienna Drosophila Resource Center for various fly strains. The mass spectrometry data were obtained from an Orbitrap mass spectrometer funded, in part, by NIH grants NS046593 and 1S10OD025047-01 for the support of proteomics research at Rutgers Newark campus. C.J.G. was supported by a predoctoral fellowship to promote diversity from the NIH (F31-GM125363). C.O. was supported by funds from the Summer Program for Under-Represented Students (SPURS) under the auspices of the Department of Physiology and Cellular Biophysics at Columbia University to promote diversity. Work in the Owusu-Ansah laboratory is supported by a Provost Junior Faculty Grant to support Columbia{\textquoteright}s diversity efforts, an Irma T. Hirschl Trust Scientist Award, and NIH grants AR077312 (R21) and GM124717 (R35). Publisher Copyright: Copyright {\textcopyright} 2022 The Authors,",
year = "2022",
month = may,
doi = "10.1126/sciadv.abl8716",
language = "English (US)",
volume = "8",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "19",
}