Journal Club

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

Science

22 Oct 2026

Vol 394, Issue 6822

Structured Abstract

INTRODUCTION

Mitochondria have a pivotal role in mammalian cell death. In response to apoptotic signals, activator BH3-only proteins activate BAX and BAK, leading to mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, apoptosome assembly, and caspase-mediated apoptosis. In cells lacking apoptosome function, activation of BAX and BAK instead leads to sustained release of mitochondrial DNA (mtDNA) into the cytosol, activation of cGAS-STING–type I interferon signaling, and caspase-independent cell death. The apoptotic caspase cascade normally suppresses this innate immune pathway, rendering apoptosis immunologically silent. Given that impaired apoptosome function is common in human cancers, BAX-BAK activation–induced mtDNA efflux and immunogenic cell death may provide a new avenue for cancer therapy. However, the molecular and biochemical basis of mtDNA efflux was not understood.

RATIONALE

BAX-BAK activation–induced mtDNA efflux has been attributed to MOMP-associated mitochondrial inner membrane (MIM) herniation. After cytochrome c efflux, BAX and BAK coalesce to form macropores in the mitochondrial outer membrane (MOM), through which the MIM herniates and subsequently loses membrane integrity, resulting in mtDNA efflux. However, only a minority of herniated MIM structures lose membrane integrity, suggesting that mtDNA efflux may also involve an active biochemical process. We therefore used biochemical and genetic studies to determine whether BAK and BAX engage distinct protein complexes that differentially regulate cytochrome c and mtDNA efflux. We further examined this process in human cancer cells with impaired apoptosome function.

RESULTS

BAK and BAX, once activated by activator BH3-only proteins, assembled into two functionally distinct mitochondrial complexes. The machinery responsible for cytochrome c release probably consisted of a BAK or BAX hexamer. By contrast, we purified a preexisting 600-kD complex comprising BAK, VDAC1, VDAC2, PHB1, and PHB2, which may localize at contact sites between the MOM and MIM. Activation by BH3-only proteins appears to remodel this complex and promote recruitment of cytosolic BAX to form mtDNA-releasing machinery, which directly released mtDNA from mitoplasts. This remodeling was associated with VDAC channel closure and increased mitochondrial calcium influx. Loss of VDAC1, VDAC2, or prohibitins impaired mtDNA efflux and caspase-independent cell death without affecting MOMP or MIM herniation. Depletion of mtDNA also protected cells from this form of death, supporting a contribution of cytosolic mtDNA to cellular demise. We designated this BAX-BAK activation–induced caspase-independent cell death “baciptosis.” Baciptosis displayed necrotic morphology, lacked widespread genomic DNA fragmentation, and was accompanied by a progressive decline in ATP concentrations before cellular demise. These findings were recapitulated in apoptosome-deficient human kidney and lung cancer cells.

CONCLUSION

Our findings identify mtDNA-releasing machinery that is distinct from the cytochrome c–releasing MOMP machinery. Thus, mtDNA efflux is not simply a downstream consequence of MOMP or MIM herniation but instead involves a distinct, active biochemical process. mtDNA efflux contributes to baciptosis, a form of BAX-BAK activation–induced programmed necrosis that occurs when apoptosome function is impaired. This work provides a mechanistic basis for exploring BAX-BAK activation–induced baciptosis as a potential therapeutic avenue in apoptosome-deficient cancers.