当复合物 I 被抑制时，脯氨酸氧化支持线粒体 ATP 的产生

Proline Oxidation Supports Mitochondrial ATP Production When Complex I Is Inhibited

Keywords：proline dehydrogenase, substrate-level phosphorylation, coenzyme Q, reducing equivalent

关键词：脯氨酸脱氢酶，底物水平磷酸化，辅酶 Q，还原当量

组织：肾脏
作者：Pallag G, Nazarian S, Ravasz D, Bui D, Komlódi T, Doerrier C, Gnaiger E, Seyfried TN, Chinopoulos C
出版期刊：《ITERNATIONAL JOURNAL OF MOLECULAR MEDICINE》 2022/5/4

Abstract：

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.

文章摘要：

脯氨酸氧化为 pyrroline-5-carboxylate (P5C) 导致电子转移到线粒体中表达脯氨酸脱氢酶 (ProDH) 的泛醌。这种电子转移支持配合物 CIII 和 CIV，从而产生质子动力。 P5C 的进一步分解代谢形成谷氨酸，它为柠檬酸循环提供燃料，产生维持氧化磷酸化的还原当量。然而，由于 NAD+ 的需要，P5C 和谷氨酸分解代谢依赖于 CI 活性。 NextGen-O2k（Oroboros Instruments）用于测量各种小鼠组织的分离线粒体中的脯氨酸氧化。同时测量耗氧量、膜电位、NADH 和泛醌氧化还原状态与 ProDH 活性和 F1FO-ATPase 方向性相关。脯氨酸分解代谢产生足够高的膜电位，能够维持 F1FO-ATPase 以正向模式运行。这在 CI 抑制的小鼠肝脏和肾脏线粒体中观察到，这些线粒体表现出高水平的脯氨酸氧化和 ProDH 活性。在缺氧或当 CIII 或 CIV 被抑制时，没有观察到这种作用。 CIII 和 CIV 的 duroquinone 燃料部分再现了脯氨酸的作用。然而，过量的谷氨酸不能重现脯氨酸效应，这表明涉及从脯氨酸转化谷氨酸的上游过程。 ProDH 抑制剂四氢-2-糠酸和在较小程度上，S-5-氧代-2-四氢呋喃羧酸消除了所有脯氨酸的影响。数据表明，ProDH 指导的脯氨酸分解代谢可以产生足够的 CIII 和 CIV 质子泵，因此即使在 CI 抑制下也支持 F1FO-ATP 酶产生 ATP。

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