BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

Kate McArthur, Lachlan W. Whitehead, John M. Heddleston, Lucy Li, Benjamin S. Padman, Viola Oorschot, Niall D. Geoghegan, Stephane Chappaz, Sophia Davidson, Hui San Chin, Rachael M. Lane, Marija Dramicanin, Tahnee L. Saunders, Canny Sugiana, Romina Lessene, Laura D. Osellame, Teng Leong Chew, Grant Dewson, Michael Lazarou, Georg RammGuillaume Lessene, Michael T. Ryan, Kelly L. Rogers, Mark F. Van Delft, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

174 Citations (Scopus)

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.

Original languageEnglish
Article numbereaao6047
Number of pages12
JournalScience
Volume359
Issue number6378
DOIs
Publication statusPublished - 23 Feb 2018

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