Dominant mutations in the mitochondrial paralogs CHCHD2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson's disease and ALS/FTD/myopathy, respectively. The mechanism by which they disrupt mitochondrial cristae, however, has been uncertain. Using the first C2/C10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/C10 are intimately linked. Similar to patients with C10 mutations, we found that C2/C10 DKO mice have disrupted mitochondrial cristae, due to cleavage of the mitochondrial shaping protein L-OPA1 by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 knock-in (KI) mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities due to both C10 mutation and C2/C10 loss. Using OMA1 activation as a functional assay, we found that C2 and C10 are partially functionally redundant, and some but not all disease-causing mutations have retained activity. Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the mt-ISR in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.

中文翻译：

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CHCHD2 和 CHCHD10 的缺失会激活 OMA1 肽酶以破坏线粒体嵴表型复制患者突变。

线粒体旁系同源物 CHCHD2 (C2) 和 CHCHD10 (C10) 的显性突变最近被确定为分别导致帕金森病和 ALS/FTD/肌病。然而，它们破坏线粒体嵴的机制尚不确定。使用第一个 C2/C10 双敲除 (DKO) 小鼠，我们报告 C10 发病机制和 C2/C10 的正常功能密切相关。与具有 C10 突变的患者相似，我们发现 C2/C10 DKO 小鼠的线粒体嵴被破坏，这是由于应激诱导的肽酶 OMA1 对线粒体成形蛋白 L-OPA1 的切割。发现 OMA1 在突变 C10 敲入 (KI) 小鼠的受影响组织中类似地被激活，这表明 L-OPA1 切割是由于 C10 突变和 C2/C10 缺失引起的嵴异常的新机制。使用 OMA1 激活作为功能测定，我们发现 C2 和 C10 在功能上是部分冗余的，并且一些但不是所有引起疾病的突变都保留了活性。最后，C2/C10 DKO 小鼠对突变 C10 KI 小鼠进行部分表型复制，导致心肌病的发展和受影响组织中 mt-ISR 的激活，将突变 C10 发病机制与 C2/C10 功能联系起来。