Proline Oxidation Supports Mitochondrial ATP Production When Complex I Is Inhibited
| Autor: | Gergely Pallag, Sara Nazarian, Dora Ravasz, David Bui, Timea Komlódi, Carolina Doerrier, Erich Gnaiger, Thomas N. Seyfried, Christos Chinopoulos |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Adenosine Triphosphatases
Electron Transport Complex I Proline proline dehydrogenase substrate-level phosphorylation coenzyme Q reducing equivalent Ubiquinone Organic Chemistry Glutamic Acid General Medicine Catalysis Mitochondria Computer Science Applications Inorganic Chemistry Mice Adenosine Triphosphate Proline Oxidase Animals Physical and Theoretical Chemistry Molecular Biology Spectroscopy |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 9; Pages: 5111 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23095111 |
| Popis: | The oxidation of proline to pyrroline-5-carboxylate (P5C) leads to the transfer of electrons to ubiquinone in mitochondria that express proline dehydrogenase (ProDH). This electron transfer supports Complexes CIII and CIV, thus generating the protonmotive force. Further catabolism of P5C forms glutamate, which fuels the citric acid cycle that yields the reducing equivalents that sustain oxidative phosphorylation. However, P5C and glutamate catabolism depend on CI activity due to NAD+ requirements. NextGen-O2k (Oroboros Instruments) was used to measure proline oxidation in isolated mitochondria of various mouse tissues. Simultaneous measurements of oxygen consumption, membrane potential, NADH, and the ubiquinone redox state were correlated to ProDH activity and F1FO-ATPase directionality. Proline catabolism generated a sufficiently high membrane potential that was able to maintain the F1FO-ATPase operation in the forward mode. This was observed in CI-inhibited mouse liver and kidney mitochondria that exhibited high levels of proline oxidation and ProDH activity. This action was not observed under anoxia or when either CIII or CIV were inhibited. The duroquinone fueling of CIII and CIV partially reproduced the effects of proline. Excess glutamate, however, could not reproduce the proline effect, suggesting that processes upstream of the glutamate conversion from proline were involved. The ProDH inhibitors tetrahydro-2-furoic acid and, to a lesser extent, S-5-oxo-2-tetrahydrofurancarboxylic acid abolished all proline effects. The data show that ProDH-directed proline catabolism could generate sufficient CIII and CIV proton pumping, thus supporting ATP production by the F1FO-ATPase even under CI inhibition. |
| Databáze: | OpenAIRE |
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