Journal
SCIENCE ADVANCES
Volume 8, Issue 19, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abl8716
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Funding
- NIH [NS046593, 1S10OD025047-01, F31-GM125363, AR077312, GM124717]
- Summer Program for Under-Represented Students (SPURS) under Department of Physiology and Cellular Biophysics at Columbia University
- Provost Junior Faculty Grant
- Irma T. Hirschl Trust Scientist Award
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This study reveals that disruption of the mitochondrial NADPH-generating enzyme IDH2 in Drosophila flight muscles leads to elevated levels of reactive oxygen species (ROS) and impairment of oxidative phosphorylation system (OXPHOS) assembly. The impairment begins with inhibited biosynthesis of the matrix domain of CI and affects multiple OXPHOS complexes. Despite the activation of compensatory mechanisms, ferroptotic cell death occurs, implicating hydrogen peroxide as the signaling molecule involved. IDH2 plays a role in modulating CI assembly and ultimately the entire OXPHOS.
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.
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