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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.

CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10