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Complex I activity in hypoxia: implications for oncometabolism.

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

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Hypoxic cancer cells utilize residual Complex I activity to regenerate NAD+, fueling glutaminolysis for energy. This suggests Complex I inhibitors may treat cancers even with impaired oxidative phosphorylation (OXPHOS).

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Area of Science:

  • Biochemistry
  • Cancer Metabolism
  • Oncology

Background:

  • Solid tumors often contain hypoxic regions where cancer cells cannot perform oxidative phosphorylation (OXPHOS).
  • Despite oxygen deprivation, these cells maintain metabolic activity dependent on NAD+.
  • Residual Complex I activity, independent of oxygen, plays a crucial role in NAD+ regeneration.

Purpose of the Study:

  • To investigate the role of persistent Complex I activity in hypoxic cancer cells.
  • To elucidate the NAD+-dependent metabolic pathways supporting cancer cell survival under hypoxia.
  • To explore the therapeutic potential of targeting Complex I in OXPHOS-deficient cancers.

Main Methods:

  • Review of biochemical pathways and enzyme activities under hypoxic conditions.
  • Analysis of NAD+/NADH redox balance and its impact on metabolic flux.
  • Examination of glutaminolysis and related oncometabolic pathways.

Main Results:

  • Residual Complex I oxidizes NADH to NAD+ even without oxygen.
  • Regenerated NAD+ fuels the alpha-ketoglutarate dehydrogenase complex in glutaminolysis.
  • Substrate-level phosphorylation via succinyl-CoA ligase produces high-energy phosphates, partially compensating for OXPHOS deficiency.

Conclusions:

  • Hypoxic cancer cells rely on Complex I-mediated NAD+ regeneration to sustain glutaminolysis.
  • This metabolic adaptation allows for partial energy compensation despite impaired OXPHOS.
  • Targeting Complex I may be a viable strategy for treating cancers with compromised OXPHOS.