2026年10月22日，美国纪念斯隆-凯特琳癌症中心Emily H. Cheng等科学家在《科学》（Science）发表研究，揭示了BAK和BAX形成多蛋白复合物驱动mtDNA外流和caspase非依赖性细胞死亡的机制。

凋亡调控因子BAX和BAK一旦被激活，便形成同源寡聚体，触发线粒体外膜通透化（MOMP），激活凋亡体和caspase。BAX-BAK的激活若不伴随凋亡体激活，则会触发线粒体DNA（mtDNA）的持续外流和caspase非依赖性细胞死亡。然而，mtDNA外流的分子基础仍不清楚。研究人员纯化了一个大分子复合物，该复合物由BAK、BAX、激活型BH3-only分子、电压依赖性阴离子通道1和2（VDAC1和VDAC2）以及抑制素组成，能够从线粒体基质中释放mtDNA。BAX-BAK激活导致VDAC关闭、线粒体钙内流和mtDNA外流。VDAC1、VDAC2或抑制素的缺失，可阻止BAX-BAK激活诱导的mtDNA外流和caspase非依赖性细胞死亡，而不影响MOMP或线粒体内膜突出。这些发现支持细胞色素c和mtDNA外流由不同的BAX-BAK复合物差异调控。

附：英文原文

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

Author: 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

Issue&Volume: 2026-10-22

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.

DOI: 10.1126/science.aea2181

Source: https://www.science.org/doi/10.1126/science.aea2181