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Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation\u2013induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome\n                    <jats:italic toggle=\"yes\">c<\/jats:italic>\n                    and mtDNA efflux by distinct BAX-BAK complexes.\n                  <\/jats:p>","DOI":"10.1126\/science.aea2181","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:00:48Z","timestamp":1792692048000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death"],"prefix":"10.1126","volume":"394","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9953-4840","authenticated-orcid":true,"given":"Shaoyuan","family":"Yang","sequence":"first","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-6373","authenticated-orcid":true,"given":"Hyungjin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanghong","family":"Liao","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Ta","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8904-8239","authenticated-orcid":true,"given":"Ho-Chou","family":"Tu","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6719-9005","authenticated-orcid":true,"given":"Shriram","family":"Ramani","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3296-3787","authenticated-orcid":true,"given":"Zih-Yu","family":"Li","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5593-1414","authenticated-orcid":true,"given":"Nobuhiro","family":"Tanno","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-0551","authenticated-orcid":true,"given":"James J.","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-2648","authenticated-orcid":true,"given":"Emily H.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA."},{"name":"Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA."},{"name":"Weill Cornell Medicine, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","first-page":"2922","article-title":"The expanding role of mitochondria in apoptosis","volume":"15","author":"Wang X.","year":"2001","unstructured":"X. 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