CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10
CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10
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DOI：
10.1093/hmg/ddy270
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发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Narendra, Derek P.
中科院分区：
文献类型：
--
作者：
Huang, Xiaoping;Wu, Beverly P.;Narendra, Derek P.
线粒体蛋白CHCHD2和CHCHD10的突变分别导致常染色体显性遗传性帕金森病(PD)和肌萎缩侧索硬化症/额颞叶痴呆(ALS/FTD)。利用新产生的CHCHD2、CHCHD10和CHCHD2/10双基因敲除细胞系，我们发现这些蛋白在功能上部分冗余，类似地分布在线粒体的各个区域，并形成异二聚体。出乎意料的是，我们还发现CHCHD2/CHCHD10异二聚化增加，以响应线粒体应激。这种增加是由蛋白质的稳定性和相互亲和力的差异驱动的：CHCHD2优先通过线粒体膜电位的丧失稳定，而CHCHD10的寡聚依赖于CHCHD2的表达。利用CHCHD10齐聚对CHCHD2的依赖性，我们建立了异源二聚体掺入实验，证明了CHCHD2和具有致病突变的CHCHD10容易形成异源二聚体。由于我们还发现这两个蛋白在人类黑质和皮质锥体神经元中高表达，突变的CHCHD2和CHCHD10可能在PD和ALS/FTD的发病机制中直接与其野生型同源基因相互作用。综上所述，这些发现表明，CHCHD2和CHCHD10在稳定性和相互亲和力方面的差异调节了它们在应对线粒体窘迫时的异二聚化，揭示了PD和ALS/FTD发病机制之间的意外联系。
Mutations in paralogous mitochondrial proteins CHCHD2 and CHCHD10 cause autosomal dominant Parkinson Disease (PD) and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD), respectively. Using newly generated CHCHD2, CHCHD10 and CHCHD2/10 double knockout cell lines, we find that the proteins are partially functionally redundant, similarly distributed throughout the mitochondrial cristae, and form heterodimers. Unexpectedly, we also find that CHCHD2/CHCHD10 heterodimerization increases in response to mitochondrial stress. This increase is driven by differences in the proteins' stability and mutual affinity: CHCHD2 is preferentially stabilized by loss of mitochondrial membrane potential, and CHCHD10 oligomerization depends on CHCHD2 expression. Exploiting the dependence of CHCHD10 oligomerization on CHCHD2, we developed a heterodimer incorporation assay and demonstrate that CHCHD2 and CHCHD10 with disease-causing mutations readily form heterodimers. As we also find that both proteins are highly expressed in human Substantia nigra and cortical pyramidal neurons, mutant CHCHD2 and CHCHD10 may directly interact with their wild-type paralogs in the context of PD and ALS/FTD pathogenesis. Together, these findings demonstrate that differences in the stability and mutual affinity of CHCHD2 and CHCHD10 regulate their heterodimerization in response to mitochondrial distress, revealing an unanticipated link between PD and ALS/FTD pathogenesis.