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 Ramm; Guillaume Lessene; Michael T Ryan; Kelly L Rogers; Mark F van Delft; Benjamin T Kile

Journal article

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 Ramm Show all

SCIENCE | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2018

DOI: 10.1126/science.aao6047

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 al..

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University of Melbourne Researchers

Marija Dramicanin Author Medical Biology (w.e.h.i.)

Guillaume Lessene Author Medical Biology (w.e.h.i.)

Niall Geoghegan Author Medical Biology (w.e.h.i.)

Lachlan Whitehead Author Medical Biology (w.e.h.i.)

Kelly Rogers Author Medical Biology (w.e.h.i.)

Grants

Awarded by Australian Federal Government Postgraduate Award

Awarded by ARC Future Fellowship

Awarded by ARC

Awarded by Independent Research Institutes Infrastructure Support Scheme Grant from the Australian National Health and Medical Research Council (NHMRC)

Awarded by Ramaciotti Foundation

Awarded by Australian Research Council

Funding Acknowledgements

Supported by an Australian Federal Government Postgraduate Award (K.M.); Project Grants (1077750, 1106471, 1078924, 1083077), Program Grants (1016647, 1113577, 1113133), Fellowships (1063008, B.T.K.; 1117089, G.L.), an ARC Future Fellowship (160100063, M.L.), an ARC Discovery Grant (DP16012176, M.T.R.), and an Independent Research Institutes Infrastructure Support Scheme Grant (361646) from the Australian National Health and Medical Research Council (NHMRC); the Australian Cancer Research Fund; and a Victorian State Government Operational Infrastructure Support Grant. The Advanced Imaging Center at Janelia Research Campus is jointly supported by the Howard Hughes Medical Institute and the Gordon and Betty Moore Foundation. The Monash Ramaciotti Centre for Cryo-Electron Microscopy is supported by the Ramaciotti Foundation (CD11/1958) and the Australian Research Council (LE120100090 and LE100100165).