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

Dora Ravasz1, David Bui1, Sara Nazarian1

  • 1Department of Biochemistry, Semmelweis University, Budapest, 1094, Hungary.

Scientific Reports
|January 19, 2024
PubMed

Insights

Under anoxia, Complex I uses quinones to oxidize NADH, regenerating NAD+ for crucial metabolic pathways like glutamate catabolism and supporting mitochondrial substrate-level phosphorylation (mtSLP) when oxidative phosphorylation is halted.

Area of Science:

  • Mitochondrial physiology
  • Cellular metabolism
  • Biochemistry

Background:

  • Anoxia inhibits oxidative phosphorylation (OXPHOS), leading to reduced compound buildup in mitochondria.
  • This buildup impedes dehydrogenase activity, disrupting cellular energy production.

Purpose of the Study:

  • To investigate mitochondrial function under acute anoxia.
  • To elucidate the role of Complex I and quinones in maintaining metabolic activity during oxygen deprivation.

Main Methods:

  • Real-time measurement of oxygen concentration, NADH autofluorescence, mitochondrial membrane potential, and ubiquinone reduction extent.
  • 13C metabolic tracing and untargeted metabolite analysis during anoxia.
  • Utilized site-specific inhibitors of the electron transfer system.

Main Results:

  • Complex I utilizes endogenous quinones to oxidize NADH under anoxia.
  • NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex, supporting mitochondrial substrate-level phosphorylation (mtSLP) and producing succinate.
  • Complex II functions bidirectionally, supplying quinones to Complex I and reducing fumarate to succinate.

Conclusions:

  • Quinone provision to Complex I is critical for oxidizing NADH during anoxia.
  • This process maintains glutamate catabolism and mtSLP in the absence of OXPHOS.
  • Highlights alternative metabolic strategies in mitochondria under stress conditions.

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