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The pathophysiology of MTS remains poorly understood. To investigate the molecular mechanisms underlying MTS, we established induced pluripotent stem cells (iPSCs) from a male MTS patient carrying a novel\n                    <jats:italic>TIMM8A<\/jats:italic>\n                    mutation (c.225-229del, p.Q75fs95*), referred to as MTS-iPSCs. To generate an isogenic control, we introduced the same mutation into healthy control iPSCs (CTRL-iPSCs) using the Clustered Regularly Interspaced Short Palindromic Repeats\/CRISPR-associated protein 9 (CRISPR\/Cas9), resulting in mutant iPSCs (MUT-iPSCs). We differentiated the three iPSC lines into neurons and evaluated their mitochondrial function and neuronal development. Both MTS- and MUT-iPSCs exhibited impaired neuronal differentiation, characterized by smaller somata, fewer branches, and shorter neurites in iPSC-derived neurons. Additionally, these neurons showed increased susceptibility to apoptosis under stress conditions, as indicated by elevated levels of cytochrome c and cleaved caspase-3. Mitochondrial function analysis revealed reduced protein levels and activity of complex IV, diminished ATP synthesis, and increased reactive oxygen species (ROS) generation in MTS- and MUT-neurons. Furthermore, transmission electron microscopy revealed mitochondrial fragmentation in MTS-neurons. RNA sequencing identified differentially expressed genes (DEGs) involved in axonogenesis, synaptic activity, and apoptosis-related pathways. Among these DEGs,\n                    <jats:italic>coiled-coil-helix-coiled-coil-helix domain-containing 2<\/jats:italic>\n                    (\n                    <jats:italic>CHCHD2<\/jats:italic>\n                    ), which encodes a mitochondrial IMS protein essential for mitochondrial homeostasis, was significantly downregulated in MTS-neurons. Western blot analysis confirmed decreased CHCHD2 protein levels in both MTS- and MUT-neurons. Overexpression of CHCHD2 rescued mitochondrial dysfunction and promoted neurite elongation in MTS-neurons, suggesting that CHCHD2 acts as a downstream effector of TIMM8a in the pathogenesis of MTS. In summary, loss-of-function of TIMM8a leads to a downstream reduction in CHCHD2 levels, collectively impairing neurogenesis by disrupting mitochondrial homeostasis.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07472-9","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T15:01:41Z","timestamp":1741791701000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["CHCHD2 rescues the mitochondrial dysfunction in iPSC-derived neurons from patient with Mohr-Tranebjaerg syndrome"],"prefix":"10.1038","volume":"16","author":[{"given":"Yihua","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zirui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiling","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhirong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9205-1603","authenticated-orcid":false,"given":"Hailiang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongming","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6162-400X","authenticated-orcid":false,"given":"Yafang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"7472_CR1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/ajmg.1320090110","volume":"9","author":"PK Jensen","year":"1981","unstructured":"Jensen PK. Nerve deafness: optic nerve atrophy, and dementia: a new X-linked recessive syndrome? Am J Med Genet. 1981;9:55\u201360.","journal-title":"Am J Med Genet"},{"key":"7472_CR2","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1136\/jmg.32.4.257","volume":"32","author":"L Tranebjaerg","year":"1995","unstructured":"Tranebjaerg L, Schwartz C, Eriksen H, Andreasson S, Ponjavic V, Dahl A, et al. A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. J Med Genet. 1995;32:257\u201363.","journal-title":"J Med Genet"},{"key":"7472_CR3","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/ng1096-177","volume":"14","author":"H Jin","year":"1996","unstructured":"Jin H, May M, Tranebjaerg L, Kendall E, Font\u00e1n G, Jackson J, et al. A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. 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Ethics committee approval number: NFEC-2023-428. All participants provided informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"173"}}