BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
- Author(s)
- McArthur, K; Whitehead, LW; Heddleston, JM; Li, L; Padman, BS; Oorschot, V; Geoghegan, ND; Chappaz, S; Davidson, S; San Chin, H; Lane, RM; Dramicanin, M; Saunders, TL; Sugiana, C; Lessene, R; Osellame, LD; Chew, TL; Dewson, G; Lazarou, M; Ramm, G; Lessene, G; Ryan, MT; Rogers, KL; van Delft, MF; Kile, BT;
- Journal Title
- Science
- Publication Type
- Journal Article
- Abstract
- Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce mitochondrial outer membrane permeabilization, leading to cytochrome c release and activation of apoptotic caspases. In the absence of active caspases, mitochondrial DNA (mtDNA) triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon. How cGAS gains access to mtDNA remains unclear. We used live-cell lattice light-sheet microscopy to examine the mitochondrial network in mouse embryonic fibroblasts. We found that after BAK/BAX activation and cytochrome c loss, the mitochondrial network broke down and large BAK/BAX pores appeared in the outer membrane. These BAK/BAX macropores allowed the inner mitochondrial membrane to herniate into the cytosol, carrying with it mitochondrial matrix components, including the mitochondrial genome. Apoptotic caspases did not prevent herniation but dismantled the dying cell to suppress mtDNA-induced innate immune signaling.
- Publisher
- AAAS
- Research Division(s)
- Systems Biology And Personalised Medicine; Chemical Biology; Cell Signalling And Cell Death; Cancer And Haematology
- PubMed ID
- 29472455
- Publisher's Version
- https://doi.org/10.1126/science.aao6047
- NHMRC Grants
- NHMRC/1077750, NHMRC/1106471, NHMRC/1078924, NHMRC/1083077, NHMRC/1016647, NHMRC/1113577, NHMRC/1113133, NHMRC/1117089,
- ARC Grants
- ARC/160100063,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-03-19 10:02:40
Last Modified: 2018-03-19 12:06:48