Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia

Dora Ravasz, David Bui, Sara Nazarian, Gergely Pallag, Noemi Karnok, Jennie Roberts, Bryan P Marzullo, Daniel A Tennant, Bennett Greenwood, Alex Kitayev, Collin Hill, Timea Komlódi, Carolina Doerrier, Kristyna Cunatova, Erika Fernandez-Vizarra, Erich Gnaiger, Michael A Kiebish, Alexandra Raska, Krasimir Kolev, Bence CzumbelNiven R Narain, Thomas N Seyfried, Christos Chinopoulos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in the mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in isolated mitochondria in real-time, we demonstrate that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. 13C metabolic tracing or untargeted analysis of metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system showed that NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Complex II operated amphidirectionally during the anoxic event, providing quinones to Complex I and reducing fumarate to succinate. Our results highlight the importance of quinone provision to Complex I oxidizing NADH maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.

Original languageEnglish
Article number1729
JournalScientific Reports
Volume14
Issue number1
DOIs
Publication statusPublished - 19 Jan 2024

Bibliographical note

© 2024. The Author(s).

Keywords

  • Humans
  • NAD/metabolism
  • Mitochondria/metabolism
  • Electron Transport Complex I/metabolism
  • Quinones/metabolism
  • Oxidative Phosphorylation
  • Succinates/metabolism
  • Hypoxia/metabolism
  • Oxidation-Reduction

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