Journal
CELL CHEMICAL BIOLOGY
Volume 29, Issue 4, Pages 636-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2021.10.010
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Funding
- Medical Research Council [MC_U105663142, MC_UU_00015/7, MR/P000320/1]
- Wellcome Trust [WT110158/Z/15/Z, 110159/Z/15/Z, RG88195, 202905/Z/16/Z, 206171/Z/17/Z]
- Swedish Research Council [2018-00623]
- University of Glasgow
- Swedish Research Council [2018-00623] Funding Source: Swedish Research Council
- Wellcome Trust [202905/Z/16/Z, 206171/Z/17/Z] Funding Source: Wellcome Trust
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This study found that Cys39 of ND3 is exposed in complex I during mitochondrial respiration, which has significant implications for our understanding of the A/D transition and the mechanism of complex I.
Mammalian complex I can adopt catalytically active (A-) or deactive (D-) states. A defining feature of the reversible transition between these two defined states is thought to be exposure of the ND3 subunit Cys39 residue in the D-state and its occlusion in the A-state. As the catalytic A/D transition is important in health and disease, we set out to quantify it by measuring Cys39 exposure using isotopic labeling and mass spectrometry, in parallel with complex I NADH/CoQ oxidoreductase activity. To our surprise, we found significant Cys39 exposure during NADH/CoQ oxidoreductase activity. Furthermore, this activity was unaffected if Cys39 alkylation occurred during complex I-linked respiration. In contrast, alkylation of catalytically inactive complex I irreversibly blocked the reactivation of NADH/CoQ oxidoreductase activity by NADH. Thus, Cys39 of ND3 is exposed in complex I during mitochondrial respiration, with significant implications for our understanding of the A/D transition and the mechanism of complex I.
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