Interrogating neurodegeneration-linked CHCHD2 and CHCHD10 and their mitochondrial interaction network

Authors

• TH Huang
• N Randolph
• XP Huang
• B Wu
• DP Narendra

Abstract

Dominant mutations in the paralogs CHCHD2 (C2) and CHCHD10 (C10) cause neurodegenerative disease. These nuclear-encoded small mitochondrial proteins localize to the intermembrane space side of mitochondrial cristae. Their functions are crucial for maintaining cristae structure and oxidative phosphorylation (OXPHOS). However, the detailed molecular mechanism of their action has not been fully characterized. Using a novel antibody and C2/C10 double knockout (DKO) cell lines and mouse models, we established steady interactors of C2/C10 in cell culture and in vivo through affinity purification mass spectrometry. We confirmed several previously published interactors and established that OXPHOS subunits are major interactors. By using KO cell lines of individual interactors, we found that the number of C2/C10 interactors was dramatically increased in cell lines with disrupted mitochondrial cristae, including TAZ, SLP2, and MIC60 KO lines. We knocked out C2/C10 from these lines to produce triple knockout (TKO) lines and found that the protein abundance of the increased interactors is downregulated in TKO lines. These TKO cells exhibit severe growth defects in galactose medium, as they can only rely on OXPHOS to produce ATP. In addition, we identified that FIS1 and DRP1 are crucial for DKO cell survival by using a genome-wide lethality screen. It suggests that the disruption of FIS1-DRP1-mediated mitochondrial fission machinery impacts DKO cell survival. Therefore, we hypothesize that C2/C10 may have chaperone-like functions by stabilizing their interactors to maintain mitochondrial function. This function of C2/C10 may be conditionally essential in the setting of cristae disruption or failure of mitochondrial quality control fission.

Scientific Focus Area: Neuroscience

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