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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates
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Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates

机译：缺氧/复氧过程中的线粒体功能障碍及其通过柠檬酸循环中间体的厌氧代谢进行纠正

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Kidney proximal tubule cells developed severe energy deficits during hypoxia/reoxygenation not attributable to cellular disrup- tion, 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 ll and IV. This was accompanied by diminished mitochondrial membrane potential . The energy deficit. respiratory inhibition, and loss of △Ψm were strongly ameliorated by provision of alpha-ketoglutarate plus aspartate (αKG/ASP) supplements during either hypoxia or only during reoxygenation. Measurements of 13C-labeled metabolites in [3-~13C]aspartate-treated cells indicated the operation of anaer- obic pathways of αKG/ASP metabolism to generate ATP. yielding succinate as end product. Anaerobic metabolism of αKG/ASP also mitigated the loss of △Ψm. that occurred during hypoxia before reoxygenation. Rotenone, but not antimycin or oligomycin, pre- vented this effect, indicating that electron transport in complex I, rather than F_1F_o-ATPase activity, had been responsible for main- tenance of △Ψm bY the substrates. Thus. tubule cells subjected to hypoxia/reoxygenation can have persistent energy deficits asso- ciated with complex l dysfunction for substantial periods of time before onset of the mitochondrial permeability transition and/or Ioss 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 △Ψm via electron transport in complex l. 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.
机译：肾脏近端肾小管细胞在缺氧/复氧过程中出现严重的能量不足，这与细胞功能紊乱，嘌呤前体缺乏，线粒体通透性转变无关。或细胞色素丢失c。复氧细胞显示出复杂I底物的呼吸减少。但在配合物II和IV处电子给体的损害最小或没有损害。这伴随着线粒体膜电位的降低。能量不足。在缺氧或仅在复氧期间，通过补充α-酮戊二酸和天冬氨酸（αKG/ ASP）补充剂可大大改善呼吸抑制和△Ψm的丧失。在[3-〜13C]天冬氨酸处理的细胞中对13C标记的代谢产物进行的测量表明，αKG/ ASP代谢的厌氧途径可产生ATP。生成琥珀酸酯作为最终产品。 αKG/ ASP的无氧代谢也减轻了△Ψm的损失。在复氧之前发生在缺氧期间。鱼藤酮可防止这种作用，但抗霉素或寡霉素则不能，表明在复合体I中电子的转运而不是F_1F_o-ATPase的活性，是由底物维持△Ψm的原因。从而。在发生线粒体通透性转变和/或细胞色素c的失活之前，经历过缺氧/复氧的肾小管细胞在相当长的一段时间内可能会伴有持续的能量缺乏，并伴有复杂的功能障碍。柠檬酸循环代谢物可预防或逆转该病，柠檬酸循环代谢物可通过线粒体内底物水平的磷酸化而厌氧产生ATP，并通过电子在复合体1中的传递保持△m。利用已知存在于其他哺乳动物组织中的线粒体能量代谢的这些厌氧途径，可以提供策略来限制线粒体功能障碍，并在缺血或缺氧引起的不可逆损伤发作之前进行细胞修复。

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