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

  • Science. 2018 Feb 23;359(6378):eaao6047. doi: 10.1126/science.aao6047.
Kate McArthur  1  2  3 ,  Lachlan W Whitehead  4  2 ,  John M Heddleston  5 ,  Lucy Li  4 ,  Benjamin S Padman  6 ,  Viola Oorschot  7 ,  Niall D Geoghegan  4  2 ,  Stephane Chappaz  4  2  3 ,  Sophia Davidson  4 ,  Hui San Chin  4 ,  Rachael M Lane  3 ,  Marija Dramicanin  4  2 ,  Tahnee L Saunders  3 ,  Canny Sugiana  3 ,  Romina Lessene  4  2 ,  Laura D Osellame  6 ,  Teng-Leong Chew  5 ,  Grant Dewson  4  2 ,  Michael Lazarou  6 ,  Georg Ramm  6  7 ,  Guillaume Lessene  4  2  8 ,  Michael T Ryan  6 ,  Kelly L Rogers  4  2 ,  Mark F van Delft  4  2 ,  Benjamin T Kile  1  2  3
Affiliations
  • 1. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [email protected] [email protected].
  • 2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • 3. Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
  • 4. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 5. Advanced Imaging Center, Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.
  • 6. Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
  • 7. Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, Victoria, Australia.
  • 8. Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.
PMID: 29472455 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 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.