File:Schematic-model-of-wild-type-versus-absent-or-mutant-CHCHD10-in-neurons.jpg

English: Schematic model of wild-type versus absent or mutant CHCHD10 in neurons. ( a ) In healthy neurons (green, left), CHCHD10 is normally present in the intermembrane space of mitochondria, which functions to maintain mitochondrial morphology and synaptic integrity. Upon mitochondrial stress (that is, oxidative or hypoxic), CHCHD10 retrogradely signals to the nucleus, a process facilitated by its binding to TDP-43. Nuclear CHCHD10 then promotes the transcription of mitochondrial targeted nuclear genes (that is, COX4.2, NDUFB3 and NDUFB6), which facilitates rebalancing of mitochondrial function and synaptic integrity. Meanwhile, the binding of wild-type CHCHD10 to TDP-43 prevents the exit of TDP-43 from the nucleus to cytoplasm. ( b ) In diseased neurons (brown, right), the depletion of CHCHD10 or expression of FTD/ALS mutant CHCHD10 fails to properly maintain mitochondrial morphology, thereby promoting mitochondrial fission and impairing synaptic integrity. The increase in mitochondrial stress also constitutively reduces mitochondrial CHCHD10. While mutant CHCHD10 is capable of binding to TDP-43, it is unable to effectively block the nuclear exit of TDP-43 from the nucleus to cytoplasm (similar to the absence of CHCHD10). Meanwhile, the absence of CHCHD10 reduces the transcription of mitochondrial targeted nuclear genes, whereas the increased transcription of mitochondrial targeted nuclear genes by mutant CHCHD10 is insufficient to overcome the ongoing damage incurred in mitochondria and by cytoplasmic accumulation of TDP-43, thereby compromising synaptic integrity. In the heterozygous mutant state, FTD/ALS mutations likely function primarily in a dominant negative manner, which compromises the function of endogenous CHCHD10.