Department Biology II, Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany.
Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):E2967-76. doi: 10.1073/pnas.1303872110. Epub 2013 Jul 22.
Mitochondrial morphology changes in response to various stimuli but the significance of this is unclear. In a screen for mutants with abnormal mitochondrial morphology, we identified MMA-1, the Caenorhabditis elegans homolog of the French Canadian Leigh Syndrome protein LRPPRC (leucine-rich pentatricopeptide repeat containing). We demonstrate that reducing mma-1 or LRPPRC function causes mitochondrial hyperfusion. Reducing mma-1/LRPPRC function also decreases the activity of complex IV of the electron transport chain, however without affecting cellular ATP levels. Preventing mitochondrial hyperfusion in mma-1 animals causes larval arrest and embryonic lethality. Furthermore, prolonged LRPPRC knock-down in mammalian cells leads to mitochondrial fragmentation and decreased levels of ATP. These findings indicate that in a mma-1/LRPPRC-deficient background, hyperfusion allows mitochondria to maintain their functions despite a reduction in complex IV activity. Our data reveal an evolutionary conserved mechanism that is triggered by reduced complex IV function and that induces mitochondrial hyperfusion to transiently compensate for a drop in the activity of the electron transport chain.
线粒体形态会响应各种刺激而发生变化，但这一现象的意义尚不清楚。在筛选具有异常线粒体形态的突变体时，我们鉴定到了 MMA-1，这是秀丽隐杆线虫中法裔加拿大 Leigh 综合征蛋白 LRPPRC（富含亮氨酸的五肽重复蛋白）的同源物。我们发现降低 mma-1 或 LRPPRC 的功能会导致线粒体过度融合。降低 mma-1/LRPPRC 的功能还会降低电子传递链复合物 IV 的活性，但不会影响细胞内的 ATP 水平。在 mma-1 动物中阻止线粒体过度融合会导致幼虫停滞和胚胎致死。此外，在哺乳动物细胞中延长 LRPPRC 的敲低会导致线粒体碎片化和 ATP 水平降低。这些发现表明，在 mma-1/LRPPRC 缺陷背景下，过度融合使线粒体能够在复合物 IV 活性降低的情况下维持其功能。我们的数据揭示了一种进化保守的机制，该机制由复合物 IV 功能降低触发，并诱导线粒体过度融合，以短暂代偿电子传递链活性的下降。
