{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:07:56Z","timestamp":1785434876597,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,14]]},"group-title":"Cell Biology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T00:00:00Z","timestamp":1765670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["2R35 GM128915-01"],"award-info":[{"award-number":["2R35 GM128915-01"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5T32HD007502-25"],"award-info":[{"award-number":["5T32HD007502-25"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2R25GM134979-06"],"award-info":[{"award-number":["2R25GM134979-06"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","award":["GT15720"],"award-info":[{"award-number":["GT15720"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>MCL-1 is a canonical anti-apoptotic protein crucial for early neurodevelopment, and its loss causes embryonic-lethal defects that other BCL-2 family proteins cannot rescue. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and uncover non-apoptotic roles in sustaining mitochondrial cristae integrity, fatty acid oxidation, and progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, destabilizing the OPA1-MICOS machinery. These structural defects are accompanied by ACSL1 displacement from the mitochondria, impaired fatty acid oxidation, lipid droplet accumulation, and reduced oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner membrane and retaining ACSL1 at the outer membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS, and ACSL1 as a critical coordinator of cristae organization, lipid metabolism, and neural progenitor fate, establishing mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlighting non-canonical MCL-1 functions as regulators of brain development.<\/jats:p>","DOI":"10.64898\/2025.12.12.694056","type":"posted-content","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T10:15:13Z","timestamp":1765707313000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological MCL-1 inhibition disrupts fatty acid oxidation and depletes neural progenitor cells"],"prefix":"10.64898","author":[{"given":"Marina R.","family":"Hanna","sequence":"first","affiliation":[{"name":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Yarbrough","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Cell and Developmental Biology, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Costanzo","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Cell and Developmental Biology, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Gil","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Murrow","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Biomedical Informatics, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1201-1394","authenticated-orcid":false,"given":"Vivian","family":"Gama","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN"},{"name":"Vanderbilt University, Cell and Developmental Biology, Nashville, TN"},{"name":"Vanderbilt University, Vanderbilt Center for Stem Cell Biology, Nashville, 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