Mitochondrial inner membrane permeabilisation enables mt DNA release during apoptosis

Abstract

During apoptosis, pro‐apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP. Such caspase‐independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS‐STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS‐STING signalling pathway. Using super‐resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP. In a temporal manner, we find that following MOMP, BAX/BAK‐mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK‐dependent MOMP. Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase‐independent cell death.

Mitochondria and pathogen immunity: from killer to firestarter

“…Indeed, they found that treatment of cells with BCL‐2 targeting drugs, called BH3 mimetics, was able to stimulate the release of the pro‐inflammatory cytokines IL‐6, IL‐8, CXCL1 and FGF‐2 in the absence of cell death. Consistent with recent findings, this pro‐inflammatory phenotype was dependent on BAX/BAK and STING (McArthur et al , ; Riley et al , ). Accordingly, they found that depleting cells of mtDNA, using a mitochondrial‐targeted viral DNase, was able to reduce IL‐6 secretion following BH3‐mimetic treatment.…”

“…Mitochondrial permeabilisation elicits inflammation in multiple ways. For instance, recent work shows that mtDNA is ejected from permeabilised mitochondria during cell death, activating cGAS‐STING‐dependent type I interferon production (McArthur et al , ; Riley et al , ). While dispensable for cell death, apoptotic caspases serve to dampen inflammation by targeting multiple cellular processes (McIlwain et al , ; Ning et al , ).…”

MIM through MOM : the awakening of Bax and Bak pores

“…In addition, although Riley et al () could not follow mtDNA release in caspase proficient conditions due to fast cell demise, McArthur et al () demonstrated that this process also takes place under caspase activation. These observations underline a faster kinetics of apoptotic cellular dismantling compared to MIMP and thus suggest that the pro‐inflammatory role of MOMP is only relevant under caspase‐deficient conditions.…”

“…How mtDNA reaches the cytosol from the mitochondrial matrix to activate cGAS/STING has long puzzled researchers. Riley et al () answer this question by (i) disclosing a role for Bax/Bak‐mediated MOMP beyond CytC release and (ii) revealing MIM permeabilization (MIMP) as a bridging element between apoptotic cell death and inflammation. They show that widening of Bax/Bak pores upon MOMP and CytC efflux facilitates the extrusion of the MIM into the cytosol and MIMP allows the release of matrix material, including mtDNA.…”

“… The mechanism whereby mitochondrial DNA (mt DNA ) is released into the cytosol and activates the cGAS / STING inflammatory pathway during Bax/Bax‐mediated apoptosis is unknown. In this issue, Riley et al () report that widening of Bax and Bak pores on the mitochondrial outer membrane ( MOM ) during apoptosis allows the extrusion of the mitochondrial inner membrane ( MIM ) into the cytosol and its permeabilization to release mt DNA independently of caspases. In this scenario, Bax and Bak emerge as key modulators of the apoptotic immunogenic response. …”