Fig. 9. Two axes of CHCHD10^S59L-induced toxicity.

a CHCHD10^S59L can generate cellular toxicity with or without WT CHCHD10 and its close paralog CHCHD2. The toxicity of the gain-of-function CHCHD10^S59L mutant is mediated by two different pathways. TDP-43 axis: Upon CHCHD10^S59L expression, TDP-43 becomes more insoluble in the cytoplasm, probably due to mitochondria-induced stresses^56,57 and accumulates in mitochondria via increased binding with CHCHD10^S59L. The toxicity generated by mitochondrial TDP-43 can be mitigated by inhibitors for TDP-43 mitochondrial translocation. PINK1 axis: in response to CHCHD10^S59L expression, PINK1 is stabilized and accumulates on mitochondria in an uncontrolled manner. PINK1 phosphorylates its downstream targets, including mitofusin, mitofilin, and Parkin, which results in significant mitochondrial fragmentation, maladaptive cristae formation, and excessive mitophagy. A positive feedback mechanism via PINK1 accumulation may accelerate these processes. Genetic or chemical modulation of this pathway can mitigate CHCHD10^S59L-induced cellular toxicity and C9orf72 G4C2 repeat-induced degeneration. Interestingly, WT CHCHD10 expression reduces CHCHD10^S59L-mediated cellular toxicity through both TDP-43 and PINK1 axes.