IDH2-mediated regulation of the biogenesis of the oxidative phosphorylation system

Anjaneyulu Murari, Naga S.V. Goparaju, Shauna Kay Rhooms, Kaniz F.B. Hossain, Felix G. Liang, Christian J. Garcia, Cindy Osei, Tong Liu, Hong Li, Richard N. Kitsis, Rajesh Patel, Edward Owusu-Ansah

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereabl8716
JournalScience Advances
Volume8
Issue number19
DOIs
StatePublished - May 2022

ASJC Scopus subject areas

  • General

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