Journal Article

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

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

2018

Overview

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 Mitochondrial DNA is released from mitochondria in apoptotic cells as a result of BAK/BAX-induced mitochondrial herniation. 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: The American Association for the Advancement of Science
• Subject: Activation / Animals / Apoptosis / Arthritis / Autoimmune diseases / BAX protein / bcl-2 Homologous Antagonist-Killer Protein - genetics / bcl-2 Homologous Antagonist-Killer Protein - metabolism / bcl-2-Associated X Protein - genetics / bcl-2-Associated X Protein - metabolism / Calcium / Caspase / Cell death / Chronic conditions / Cytochrome / Cytochrome c / Cytochromes c - metabolism / Cytoplasm / Cytosol / Damage patterns / Dengue fever / Deoxyribonucleic acid / Dismantling / DNA / DNA, Mitochondrial - metabolism / Efflux / Electron microscopy / Embryo fibroblasts / Embryos / Escape systems / Fibroblasts / Gene Knockout Techniques / Genomes / HeLa Cells / HIV / Human immunodeficiency virus / Humans / Immune clearance / Immune response / Inflammatory diseases / Inner membranes / Interferon / Irradiation / Light / Membranes / Mice / Mice, Inbred C57BL / Microscopy / Mitochondria / Mitochondria - metabolism / Mitochondrial DNA / Mitochondrial Membranes - chemistry / Mitochondrial Membranes - metabolism / Moisture content / Mortality / Networks / Oligomerization / Pore formation / Pore-forming proteins / Pores / Porosity / Protein Multimerization / Proteins / Radiation / Real time / Rheumatoid arthritis / Signal transduction / Systemic lupus erythematosus / Vector-borne diseases / Viral diseases