L-OPA1 regulates mitoflash biogenesis independently from membrane fusion.
L-OPA1 regulates mitoflash biogenesis independently from membrane fusion.
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DOI：
10.15252/embr.201642931
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发表时间：
2017-03
期刊：
影响因子：
7.7
通讯作者：
Demaurex N
中科院分区：
文献类型：
--
作者：
Rosselin M;Santo-Domingo J;Bermont F;Giacomello M;Demaurex N
视神经萎缩1（optic atrophy 1，OPA 1）融合蛋白介导的线粒体闪光是对线粒体膜电位（mitochondrial membrane potential，Δ pM）随机下降的生物能学反应，其起源尚不清楚。使用结构上不同的遗传编码的pH敏感探针，我们确认闪光是基质碱化瞬变，从而确定这些事件的pH性质，我们将其重命名为“mitophHlashes”。通过电子显微镜检查证实，位于嵴或膜间隙中的探针在Δ λ m下降或呼吸链抑制期间未报告pH值变化。Opa 1消融不会改变Δψm的波动，但会大幅降低mitopHlash/Δψm偶联的效率，该偶联通过重新表达融合缺陷型OPA 1 K301 A来恢复，并保存在缺乏外膜融合蛋白MFN 1/2或OPA 1蛋白酶的细胞中OMA 1和YME 1 L，这表明线粒体膜融合和OPA 1蛋白水解加工是可有可无的。在星形孢菌素诱导的细胞凋亡过程中，pH/Δ λ m解偶联发生较早，并通过OPA 1过表达减轻，表明OPA 1在应激条件下维持mitophHlash能力。我们认为OPA 1稳定了呼吸链超复合物的构象，使呼吸线粒体能够通过爆炸性基质pH闪光来补偿Δ λ m的下降。
Mitochondrial flashes mediated by optic atrophy 1 (OPA1) fusion protein are bioenergetic responses to stochastic drops in mitochondrial membrane potential (Δψm) whose origin is unclear. Using structurally distinct genetically encoded pH‐sensitive probes, we confirm that flashes are matrix alkalinization transients, thereby establishing the pH nature of these events, which we renamed “mitopHlashes”. Probes located in cristae or intermembrane space as verified by electron microscopy do not report pH changes during Δψm drops or respiratory chain inhibition. Opa1 ablation does not alter Δψm fluctuations but drastically decreases the efficiency of mitopHlash/Δψm coupling, which is restored by re‐expressing fusion‐deficient OPA1K301A and preserved in cells lacking the outer‐membrane fusion proteins MFN1/2 or the OPA1 proteases OMA1 and YME1L, indicating that mitochondrial membrane fusion and OPA1 proteolytic processing are dispensable. pH/Δψm uncoupling occurs early during staurosporine‐induced apoptosis and is mitigated by OPA1 overexpression, suggesting that OPA1 maintains mitopHlash competence during stress conditions. We propose that OPA1 stabilizes respiratory chain supercomplexes in a conformation that enables respiring mitochondria to compensate a drop in Δψm by an explosive matrix pH flash.
小鼠OPA1的基因结构和染色体定位：其排除在BST基因座上。
影响因子：
2.9
作者：
Delettre, C;Lenaers, G;Belenguer, P;Hamel, CP
通讯作者：
Hamel, CP