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 & 5 others Guillaume Lessene, Michael T. Ryan, Kelly L. Rogers, Mark F. Van Delft, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

McArthur, Kate ; Whitehead, Lachlan W. ; Heddleston, John M. ; Li, Lucy ; Padman, Benjamin S. ; Oorschot, Viola ; Geoghegan, Niall D. ; Chappaz, Stephane ; Davidson, Sophia ; Chin, Hui San ; Lane, Rachael M. ; Dramicanin, Marija ; Saunders, Tahnee L. ; Sugiana, Canny ; Lessene, Romina ; Osellame, Laura D. ; Chew, Teng Leong ; Dewson, Grant ; Lazarou, Michael ; Ramm, Georg ; Lessene, Guillaume ; Ryan, Michael T. ; Rogers, Kelly L. ; Van Delft, Mark F. ; Kile, Benjamin T. / BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. In: Science. 2018 ; Vol. 359, No. 6378.
@article{99c1eabc208a465085085b1a6dcd3dfb,
title = "BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis",
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.",
author = "Kate McArthur and Whitehead, {Lachlan W.} and Heddleston, {John M.} and Lucy Li and Padman, {Benjamin S.} and Viola Oorschot and Geoghegan, {Niall D.} and Stephane Chappaz and Sophia Davidson and Chin, {Hui San} and Lane, {Rachael M.} and Marija Dramicanin and Saunders, {Tahnee L.} and Canny Sugiana and Romina Lessene and Osellame, {Laura D.} and Chew, {Teng Leong} and Grant Dewson and Michael Lazarou and Georg Ramm and Guillaume Lessene and Ryan, {Michael T.} and Rogers, {Kelly L.} and {Van Delft}, {Mark F.} and Kile, {Benjamin T.}",
year = "2018",
month = "2",
day = "23",
doi = "10.1126/science.aao6047",
language = "English",
volume = "359",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science (AAAS)",
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McArthur, K, Whitehead, LW, Heddleston, JM, Li, L, Padman, BS, Oorschot, V, Geoghegan, ND, Chappaz, S, Davidson, S, Chin, HS, Lane, RM, Dramicanin, M, Saunders, TL, Sugiana, C, Lessene, R, Osellame, LD, Chew, TL, Dewson, G, Lazarou, M, Ramm, G, Lessene, G, Ryan, MT, Rogers, KL, Van Delft, MF & Kile, BT 2018, 'BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis' Science, vol. 359, no. 6378, eaao6047. https://doi.org/10.1126/science.aao6047

BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. / McArthur, Kate; Whitehead, Lachlan W.; Heddleston, John M.; Li, Lucy; Padman, Benjamin S.; Oorschot, Viola; Geoghegan, Niall D.; Chappaz, Stephane; Davidson, Sophia; Chin, Hui San; Lane, Rachael M.; Dramicanin, Marija; Saunders, Tahnee L.; Sugiana, Canny; Lessene, Romina; Osellame, Laura D.; Chew, Teng Leong; Dewson, Grant; Lazarou, Michael; Ramm, Georg; Lessene, Guillaume; Ryan, Michael T.; Rogers, Kelly L.; Van Delft, Mark F.; Kile, Benjamin T.

In: Science, Vol. 359, No. 6378, eaao6047, 23.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

AU - McArthur, Kate

AU - Whitehead, Lachlan W.

AU - Heddleston, John M.

AU - Li, Lucy

AU - Padman, Benjamin S.

AU - Oorschot, Viola

AU - Geoghegan, Niall D.

AU - Chappaz, Stephane

AU - Davidson, Sophia

AU - Chin, Hui San

AU - Lane, Rachael M.

AU - Dramicanin, Marija

AU - Saunders, Tahnee L.

AU - Sugiana, Canny

AU - Lessene, Romina

AU - Osellame, Laura D.

AU - Chew, Teng Leong

AU - Dewson, Grant

AU - Lazarou, Michael

AU - Ramm, Georg

AU - Lessene, Guillaume

AU - Ryan, Michael T.

AU - Rogers, Kelly L.

AU - Van Delft, Mark F.

AU - Kile, Benjamin T.

PY - 2018/2/23

Y1 - 2018/2/23

N2 - 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.

AB - 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.

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U2 - 10.1126/science.aao6047

DO - 10.1126/science.aao6047

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JF - Science

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