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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Venkatachalam, M. A. Weinberg, J. M. Roeser, N. F. Nissim, I. |
| Description | Author Affiliation: Weinberg JM ( Division of Nephrology, Department of Internal Medicine, University of Michigan and Veteran's Administration Medical Center, Ann Arbor, MI 48109, USA. wnberg@umich.edu); |
| Abstract | Kidney proximal tubule cells developed severe energy deficits during hypoxia/reoxygenation not attributable to cellular disruption, lack of purine precursors, the mitochondrial permeability transition, or loss of cytochrome c. Reoxygenated cells showed decreased respiration with complex I substrates, but minimal or no impairment with electron donors at complexes II and IV. This was accompanied by diminished mitochondrial membrane potential (DeltaPsi(m)). The energy deficit, respiratory inhibition, and loss of DeltaPsi(m) were strongly ameliorated by provision of alpha-ketoglutarate plus aspartate (alphaKG/ASP) supplements during either hypoxia or only during reoxygenation. Measurements of (13)C-labeled metabolites in [3-(13)C]aspartate-treated cells indicated the operation of anaerobic pathways of alphaKG/ASP metabolism to generate ATP, yielding succinate as end product. Anaerobic metabolism of alphaKG/ASP also mitigated the loss of DeltaPsi(m) that occurred during hypoxia before reoxygenation. Rotenone, but not antimycin or oligomycin, prevented this effect, indicating that electron transport in complex I, rather than F(1)F(0)-ATPase activity, had been responsible for maintenance of DeltaPsi(m) by the substrates. Thus, tubule cells subjected to hypoxia/reoxygenation can have persistent energy deficits associated with complex I dysfunction for substantial periods of time before onset of the mitochondrial permeability transition and/or loss of cytochrome c. The lesion can be prevented or reversed by citric acid cycle metabolites that anaerobically generate ATP by intramitochondrial substrate-level phosphorylation and maintain DeltaPsi(m) via electron transport in complex I. Utilization of these anaerobic pathways of mitochondrial energy metabolism known to be present in other mammalian tissues may provide strategies to limit mitochondrial dysfunction and allow cellular repair before the onset of irreversible injury by ischemia or hypoxia. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 6 |
| Volume Number | 97 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2000-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Citric Acid Cycle Anoxia Mitochondria Physiology Oxygen Metabolism Adenosine Triphosphate Animals Aspartic Acid Benzimidazoles Pharmacokinetics Carbocyanines Fluorescent Dyes Ketoglutaric Acids Kidney Tubules Membrane Potentials Ultrastructure Models, Biological Oxidative Phosphorylation Rabbits Time Factors Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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