Fig. 8

Schematic model of CHCHD10 in mitochondrial proteinopathy and synaptic function. In healthy neurons, small amounts of misfolded proteins, such as TDP-43, accumulate in the cytoplasm, some of which are imported into mitochondria. Mitochondria containing a healthy level of soluble CHCHD10^WT inhibits TDP-43 insolubility and aggregation, thereby sustaining mitochondrial health. Healthy mitochondria at the synapse facilitates long-term synaptic plasticity and motor unit function. In FTLD-TDP brains, soluble CHCHD10 declines and instead deposits as insoluble CHCHD10 aggregates with phospho-TDP-43. Mechanistically, in diseased neurons, excessive amounts of misfolded proteins, such as TDP-43 or phospho-TDP-43, accumulate in the cytoplasm, some of which are imported into mitochondria. Mitochondria containing mutant and/or misfolded CHCHD10 enhance both CHCHD10 and TDP-43 aggregation, thereby driving mitochondrial proteinopathy and dysfunction. Aggregate-harboring mitochondria may contribute to cytoplasmic inclusions upon mitochondrial damage and release of the aggregate content to the cytosol. At the synapse, proteopathic mitochondria become dysfunctional and fail to support long-term synaptic plasticity or motor unit function