BAK/BAX-mediated apoptosis triggers mitochondrial herniation and mtDNA efflux K McArthur1,2,3, L Whitehead1,2, JM Heddleston4, L Li1, BS Padman3, V Oorschot3, ND Geoghegan1,2, S Chappaz1,2,3, S Davidson1, HS Chin1, RM Lane1,3, M Dramicanin1,2, TL Saunders3, C Sugiana3, R Lessene1,2, LD Osellame3, TL Chew4, G Dewson1,2, M Lazarou3, G Ramm3, G Lessene1,2, MT Ryan3, KL Rogers1,2, MF van Delft1,2, & BT Kile1,2,3 1Walter and Eliza Hall Institute, Parkville, AUS, 2University of Melbourne, Melbourne, AUS; 3Monash University, Melbourne, AUS; 4Advanced Imaging Center, Janelia Research Campus, Ashburn, USA
Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce outer mitochondrial membrane (OMM) permeabilization, leading to cytochrome c release and activation of the apoptotic caspase cascade. In the absence of active caspases, mitochondrial (mt)DNA triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon[1,2]. However, the mechanism by which cytosolic cGAS gains access to mtDNA (which normally resides within the mitochondrial matrix) remains unclear. BAK/BAX are thought to permeabilize only the OMM, not the IMM. To address this, we examined mtDNA localisation during apoptosis using a number of microscopy techniques including live-cell lattice light-sheet microscopy, 3D structured illumination microscopy (SIM), correlative light electron microscopy (CLEM) and electron cryotomography (ECT). We show that, following BAK/BAX activation and cytochrome c loss, the mitochondrial network breaks down and large BAK/BAX pores appear in the OMM. These BAK/BAX macropores allow the IMM an outlet through which it herniates, carrying with it mitochondrial matrix components, including the mitochondrial genome. This event occurred regardless of caspase activity, and was independent of DRP1-mediated fission. To our knowledge, these data provide the first real-time documentation of mtDNA release in any setting. It will be interesting to see whether mitochondrial herniation as a phenomenon is specific to apoptosis, or perhaps represents a more general mechanism of mtDNA release in some of the many disease settings in which mtDNA signalling has been implicated.
 White et al. (2014). Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell, 159(7),1549-1562.  Rongvaux et al. (2014). Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell, 159(7),1563-1577.
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