BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death

IF 47.3 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2026-10-22 DOI:10.1126/science.aea2181

Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J. Hsieh, Emily H. Cheng

{"title":"BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death","authors":"Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J. Hsieh, Emily H. Cheng","doi":"10.1126/science.aea2181","DOIUrl":null,"url":null,"abstract":"<div >The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. 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–induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome <i>c</i> and mtDNA efflux by distinct BAX-BAK complexes.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"394 6822","pages":""},"PeriodicalIF":47.3000,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/science.aea2181","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. 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–induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.

查看原文本刊更多论文

BAK和BAX形成多蛋白复合物，驱动mtDNA外排和不依赖caspase的细胞死亡

凋亡调节因子BAX和BAK一旦被激活，形成同源寡聚物触发线粒体外膜渗透（MOMP），激活凋亡和半胱天蛋白酶。没有凋亡激活的BAX-BAK激活会引发线粒体DNA （mtDNA）的持续外排和不依赖caspase的细胞死亡。然而，mtDNA外排的分子基础仍不清楚。我们纯化了一个大分子复合物，包括BAK， BAX，激活剂BH3-only分子，电压依赖性阴离子通道1和2 (VDAC1和VDAC2)，以及从有丝分裂体中释放mtDNA的禁止物。BAX-BAK激活导致VDAC关闭、线粒体钙内流和mtDNA外排。VDAC1、VDAC2或禁用物的缺失可阻止BAX-BAK激活诱导的mtDNA外溢和caspase非依赖性细胞死亡，而不影响MOMP或线粒体内膜疝。这些发现支持不同的BAX-BAK复合物对细胞色素c和mtDNA外排的差异调节。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

期刊介绍： Science is a leading outlet for scientific news, commentary, and cutting-edge research. Through its print and online incarnations, Science reaches an estimated worldwide readership of more than one million. Science’s authorship is global too, and its articles consistently rank among the world's most cited research. Science serves as a forum for discussion of important issues related to the advancement of science by publishing material on which a consensus has been reached as well as including the presentation of minority or conflicting points of view. Accordingly, all articles published in Science—including editorials, news and comment, and book reviews—are signed and reflect the individual views of the authors and not official points of view adopted by AAAS or the institutions with which the authors are affiliated. Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit recognition by the wider scientific community and general public provided by publication in Science, beyond that provided by specialty journals. Science welcomes submissions from all fields of science and from any source. The editors are committed to the prompt evaluation and publication of submitted papers while upholding high standards that support reproducibility of published research. Science is published weekly; selected papers are published online ahead of print.