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首页> 外文期刊>Science Advances >SQR mediates therapeutic effects of H2S by targeting mitochondrial electron transport to induce mitochondrial uncoupling
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SQR mediates therapeutic effects of H2S by targeting mitochondrial electron transport to induce mitochondrial uncoupling

机译：SQR通过靶向线粒体电子传输来诱导线粒体电子传输来介导H2S的治疗效果，以诱导线粒体脱耦

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Hydrogen sulfide (Hsub2/subS) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes Hsub2/subS. Therefore, SQR is assumed to inhibit Hsub2/subS signaling. We now report that SQR-mediated oxidation of Hsub2/subS drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate–activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by Hsub2/subS. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of Hsub2/subS following intracerebral hemorrhage. To conclude, SQR mediates Hsub2/subS signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications.
机译：硫化氢（H 2 s）是气体转手和潜在的治疗剂。然而，与其治疗诉讼相关的分子靶标仍然是神秘的。硫化物 - 醌氧化还原酶（SQR）不可逆地氧化H 2 s。因此，假设SQR禁止H 2 S信令。我们现在报告的是，在线粒体复合物I的SQR介导的H 2 S驱动逆向电子传输（RET）的氧化，反过来，这反过来修复了对超氧化物产生的线粒体功能。意外地，复合物I RET，依赖于高线粒体膜电位的过程，诱导过氧化物依赖性线粒体脱象和腺苷活性蛋白激酶激酶（AMPK）的下游活化。 SQR诱导的线粒体非耦合与H 2 s的线粒体复合物IV的抑制分离。此外，SQR，复合物I或AMPK的缺失消除了脑出血后H 2 S的治疗效果。为了得出结论，SQR通过靶向线粒体电子传输来诱导线粒体电子传输以诱导线粒体的解耦，介导H H 2 S信号传导和治疗效果。此外，SQR是以广泛的临床意义开发非质子化学耦合的先前未被识别的目标。

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