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

Author:

McArthur Kate123ORCID,Whitehead Lachlan W.12ORCID,Heddleston John M.4ORCID,Li Lucy1ORCID,Padman Benjamin S.5ORCID,Oorschot Viola6ORCID,Geoghegan Niall D.12,Chappaz Stephane123,Davidson Sophia1ORCID,San Chin Hui1ORCID,Lane Rachael M.3,Dramicanin Marija12,Saunders Tahnee L.3,Sugiana Canny3,Lessene Romina12,Osellame Laura D.5,Chew Teng-Leong4,Dewson Grant12,Lazarou Michael5,Ramm Georg56ORCID,Lessene Guillaume127ORCID,Ryan Michael T.5ORCID,Rogers Kelly L.12ORCID,van Delft Mark F.12ORCID,Kile Benjamin T.123ORCID

Affiliation:

1. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

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. Advanced Imaging Center, Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.

5. Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.

6. Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, Victoria, Australia.

7. Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.

Abstract

The great escape Mitochondrial DNA (mtDNA) is a potent damage-associated molecular pattern that, if it reaches the cytoplasm or extracellular milieu, triggers innate immune pathways. mtDNA signaling has been implicated in a wide range of diseases; however, the mechanisms of mtDNA release are unclear, and the process has not been observed in real time thus far. McArthur et al. used live-cell lattice light-sheet microscopy to look at mtDNA release during intrinsic apoptosis. Activation of the pro-death proteins BAK and BAX resulted in the formation of large macro-pores in the mitochondrial outer membrane. These massive holes caused the inner mitochondrial membrane to balloon out into the cytoplasm, resulting in mitochondrial herniation. This process allowed the contents of the mitochondrial matrix, including mtDNA, to escape into the cytoplasm. Science , this issue p. eaao6047

Funder

National Health and Medical Research Council

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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