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Proline Oxidation Supports Mitochondrial ATP Production When Complex I Is Inhibited.

Gergely Pallag1, Sara Nazarian1, Dora Ravasz1

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

International Journal of Molecular Sciences
|May 14, 2022
PubMed
Summary

Proline oxidation by proline dehydrogenase (ProDH) generates mitochondrial proton pumping, supporting ATP production via Complex CIII and CIV, even when Complex CI is inhibited. This bypasses CI’s NAD+ dependency.

Keywords:
coenzyme Qproline dehydrogenasereducing equivalentsubstrate-level phosphorylation

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Area of Science:

  • Mitochondrial bioenergetics
  • Cellular metabolism

Background:

  • Proline oxidation to pyrroline-5-carboxylate (P5C) involves electron transfer to ubiquinone.
  • P5C catabolism to glutamate fuels the citric acid cycle, but requires Complex CI activity.
  • Mitochondrial function under Complex CI inhibition is not fully understood.

Purpose of the Study:

  • To investigate the role of proline oxidation in supporting mitochondrial ATP production.
  • To determine if proline catabolism can bypass Complex CI dependency.
  • To elucidate the contribution of proline dehydrogenase (ProDH) to mitochondrial bioenergetics.

Main Methods:

  • Mitochondrial respiration was measured using the NextGen-O2k system in isolated mouse liver and kidney mitochondria.
  • Simultaneous measurements included oxygen consumption, membrane potential, NADH, and ubiquinone redox state.
  • Proline dehydrogenase (ProDH) activity was assessed using specific inhibitors and substrate fueling.

Main Results:

  • Proline oxidation by ProDH generated sufficient protonmotive force to drive F1F0-ATPase in forward mode, even under Complex CI inhibition.
  • This effect was dependent on functional Complexes CIII and CIV and abolished by ProDH inhibitors.
  • Proline's effect could not be replicated by excess glutamate, indicating a role for upstream pathways.

Conclusions:

  • ProDH-mediated proline catabolism can sustain mitochondrial ATP production independently of Complex CI.
  • This pathway provides an alternative route for supporting oxidative phosphorylation.
  • Proline oxidation represents a significant bioenergetic pathway under specific metabolic conditions.