{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T19:03:54Z","timestamp":1784574234550,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,17]]},"group-title":"Molecular Biology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["DP5OD026398"],"award-info":[{"award-number":["DP5OD026398"]}]},{"name":"Klingenstein-Simons Fellowship"},{"name":"Department of Defense National Defense Science and Engineering Graduate Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Complex I (CI) is the largest and most disease-associated component of the mitochondrial electron transport chain. While many diseases are linked to defects in specific CI subunits, the extent to which non-mitochondrial proteins contribute to CI function or disease is less clear. Here, we perform genome-wide CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively. These screens identify THAP12 as a previously unrecognized transcriptional regulator of CI biogenesis. THAP12 loss selectively destabilizes CI and impairs oxidative ATP production. Mechanistically, THAP12 functions in the nucleus as a DNA-binding factor that directly activates genes required for CI assembly and iron-sulfur cluster maintenance, including NDUFAF3, NDUFAF4 and BOLA3. Patient-derived fibroblasts carrying THAP12 mutations exhibit conserved transcriptional defects and profound CI deficiency, establishing THAP12-associated neurodevelopmental disorder as a secondary mitochondrial CI disease. Finally, hypoxia rescues growth defects in THAP12-deficient cells, nominating low-oxygen therapy as a potential treatment strategy. Together, these findings identify THAP12 as a dedicated regulator of CI assembly and expand the genetic landscape of CI disease.<\/jats:p>","DOI":"10.64898\/2026.07.16.738975","type":"posted-content","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:05:16Z","timestamp":1784297116000},"source":"Crossref","is-referenced-by-count":0,"title":["The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3765-3809","authenticated-orcid":false,"given":"Brandon R.","family":"Desousa","sequence":"first","affiliation":[{"name":"Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA"},{"name":"Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA"},{"name":"Arc Institute, Palo Alto, CA 94304, USA"},{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9077-969X","authenticated-orcid":false,"given":"Yohei","family":"Abe","sequence":"additional","affiliation":[{"name":"Arc Institute, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-7019","authenticated-orcid":false,"given":"Martin","family":"Kampmann","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA"},{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha H.","family":"Jain","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA"},{"name":"Arc Institute, 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