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FTD\/ALS-linked CHCHD10 mutations and TDP-43 inclusions similarly induce mitochondrial defects in respiration, fusion\/fission, mtDNA stability, and cristae structure, while sizeable amounts of cytoplasmic TDP-43 aggregates are found in mitochondria. However, the mechanistic link between CHCHD10 and TDP-43 pathogenesis remains unclear. In this study, we present immunohistochemical and biochemical evidence demonstrating that insoluble CHCHD10 aggregates accumulate and colocalize with phospho-TDP-43 inclusions in brains of FTLD-TDP and AD patients, and that insoluble CHCHD10 levels tightly correlate with insoluble TDP-43 levels in control and FTLD-TDP brains. In an experimental exploration of this pathological phenotype, transgenic mice neuronally expressing FTD\/ALS-linked CHCHD10<jats:sup>R15L<\/jats:sup> or CHCHD<jats:sup>S59L<\/jats:sup> mutations but not CHCHD10<jats:sup>WT<\/jats:sup> transgenic mice exhibit significantly increased CHCHD10 aggregation and phospho-TDP-43 pathology, which often colocalize within the same inclusions. Such pathologies are reflected in poor functional outcomes in long-term synaptic plasticity, motor unit physiology, and behavior in CHCHD10<jats:sup>R15L<\/jats:sup> and CHCHD<jats:sup>S59L<\/jats:sup> transgenic mice. In contrast, expression of CHCHD10<jats:sup>WT<\/jats:sup> in hTDP-43 transgenic mice (TAR4;CHCHD10<jats:sup>WT<\/jats:sup>) significantly mitigates phospho-TDP-43 pathology and rescues TDP-43-induced impairments in synaptic integrity and long-term synaptic plasticity. In isolated mitochondria, the S59L mutation induces the aggregation of resident CHCHD10<jats:sup>S59L<\/jats:sup> protein as well as the aggregation and slower turnover of recombinant TDP-43 imported into mitochondria. Likewise, in an in vitro cell-free system, the S59L mutation induces the aggregation of CHCHD10<jats:sup>S59L<\/jats:sup> protein while simultaneously enhancing the aggregation of recombinant TDP-43, as evidenced by filter trap assays and atomic force microscopy. In contrast, recombinant CHCHD10<jats:sup>WT<\/jats:sup> inhibits the growth of TDP-43 aggregates. These results in human brains, transgenic mice, and in vitro systems substantiate the role of wild type and mutant CHCHD10 in modulating mitochondrial CHCHD10 and TDP-43 pathogenesis together with associated phenotypes in long-term synaptic plasticity and motor unit physiology in mice and humans.<\/jats:p>","DOI":"10.1186\/s40478-022-01386-9","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T12:11:18Z","timestamp":1656936678000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10"],"prefix":"10.1186","volume":"10","author":[{"given":"Tian","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-A. 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