Edington Alia R, Connor Olivia M, Love Abigail C, Marlar-Pavey Madeleine, Friedman Jonathan R
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
J Cell Biol. 2025 Mar 3;224(3). doi: 10.1083/jcb.202403140. Epub 2024 Dec 24.
While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.
虽然已有大量研究探讨了线粒体分裂的机制，但后生动物线粒体内的蛋白质是否在这一过程中发挥直接作用仍不清楚。此前，酵母内膜蛋白Mdm33被证明是正常线粒体形态所必需的，并被推测参与线粒体分裂。然而，尚不清楚Mdm33是否发挥直接作用，且人们认为它没有哺乳动物同源物。在这里，我们使用生物信息学方法在人类中鉴定出Mdm33的结构同源物CCDC51（也称为MITOK），其缺失所产生的表型与Mdm33缺失相同。我们发现，敲低CCDC51也会导致线粒体分裂速率降低。此外，我们在空间和时间上确定了Mdm33和CCDC51参与了一部分线粒体分裂事件。最后，我们表明CCDC51的过表达促进了其与动力相关蛋白1（Drp1）的空间结合并诱导线粒体碎片化，表明它是线粒体分裂的一个正向效应因子。总之，我们的数据揭示了Mdm33和CCDC51在功能上是保守的，并表明线粒体内的蛋白质直接参与了人类细胞中至少一部分线粒体分裂事件。
