In vivo alterations in CHCHD10 and TDP-43 proteinopathies by CHCHD10 variants are recapitulated in primary neurons, cultured cells, isolated mitochondria, and purified recombinant proteins, which collectively indicate that CHCHD10 variants directly regulate the solubility and aggregation of CHCHD10 and TDP-43 in mitochondria. The gene discussed is CHCHD10; the disease is proteostasis deficiencies.