Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease and amyotrophic lateral sclerosis/frontotemporal dementia/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, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (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 because of 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 integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.

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.

During animal locomotion or position adjustments, the visual system uses image stabilization reflexes to compensate for global shifts in the visual scene. These reflexes elicit compensatory head movements (optomotor response, OMR) in unrestrained animals or compensatory eye movements (optokinetic response, OKR) in head-fixed or unrestrained animals exposed to globally rotating striped patterns. In mice, OMR are relatively easy to observe and find broad use in the rapid evaluation of visual function. OKR determinations are more involved experimentally but yield more stereotypical, easily quantifiable results. The relative contributions of head and eye movements to image stabilization in mice have not been investigated. We are using newly developed software and apparatus to accurately quantitate mouse head movements during OMR, quantitate eye movements during OKR, and determine eye movements in freely behaving mice. We provide the first direct comparison of OMR and OKR gains (head or eye velocity/stimulus velocity) and find that the two reflexes have comparable dependencies on stimulus luminance, contrast, spatial frequency, and velocity. OMR and OKR are similarly affected in genetically modified mice with defects in retinal ganglion cells (RGC) compared with wild-type, suggesting they are driven by the same sensory input (RGC type). OKR eye movements have much higher gains than the OMR head movements, but neither can fully compensate global visual shifts. However, combined eye and head movements can be detected in unrestrained mice performing OMR, suggesting they can cooperate to achieve image stabilization, as previously described for other species. We provide the first quantitation of head gain during optomotor response in mice and show that optomotor and optokinetic responses have similar psychometric curves. Head gains are far smaller than eye gains. Unrestrained mice combine head and eye movements to respond to visual stimuli, and both monocular and binocular fields are used during optokinetic responses. Mouse OMR and OKR movements are heterogeneous under optimal and suboptimal stimulation and are affected in mice lacking ON direction-selective retinal ganglion cells.