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Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death
During apoptosis the pro-death Bcl-2 family members Bax and Bak induce mitochondrial outer membrane permeabilization (MOMP) to mediate cell death. Recently, it was shown that Bax and Bak are also required for mitochondrial permeability transition pore (MPTP)-dependent necrosis, where, in their non-o...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465034/ https://www.ncbi.nlm.nih.gov/pubmed/26061004 http://dx.doi.org/10.1371/journal.pone.0130520 |
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author | Karch, Jason Kanisicak, Onur Brody, Matthew J. Sargent, Michelle A. Michael, Demetria M. Molkentin, Jeffery D. |
author_facet | Karch, Jason Kanisicak, Onur Brody, Matthew J. Sargent, Michelle A. Michael, Demetria M. Molkentin, Jeffery D. |
author_sort | Karch, Jason |
collection | PubMed |
description | During apoptosis the pro-death Bcl-2 family members Bax and Bak induce mitochondrial outer membrane permeabilization (MOMP) to mediate cell death. Recently, it was shown that Bax and Bak are also required for mitochondrial permeability transition pore (MPTP)-dependent necrosis, where, in their non-oligomeric state, they enhance permeability characteristics of the outer mitochondrial membrane. Necroptosis is another form of regulated necrosis involving the death receptors and receptor interacting protein kinases (RIP proteins, by Ripk genes). Here, we show cells or mice deficient for Bax/Bak or cyclophilin D, a protein that regulates MPTP opening, are resistant to cell death induced by necroptotic mediators. We show that Bax/Bak oligomerization is required for necroptotic cell death and that this oligomerization reinforces MPTP opening. Mechanistically, we observe mixed lineage kinase domain-like (MLKL) protein and cofilin-1 translocation to the mitochondria following necroptosis induction, while expression of the mitochondrial matrix isoform of the antiapoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), is significantly reduced. Some of these effects are lost with necroptosis inhibition in Bax/Bak1 double null, Ppif(-/-), or Ripk3(-/-) fibroblasts. Hence, downstream mechanisms of cell death induced by necroptotic stimuli utilize both Bax/Bak to generate apoptotic pores in the outer mitochondrial membrane as well as MPTP opening in association with known mitochondrial death modifying proteins. |
format | Online Article Text |
id | pubmed-4465034 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44650342015-06-25 Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death Karch, Jason Kanisicak, Onur Brody, Matthew J. Sargent, Michelle A. Michael, Demetria M. Molkentin, Jeffery D. PLoS One Research Article During apoptosis the pro-death Bcl-2 family members Bax and Bak induce mitochondrial outer membrane permeabilization (MOMP) to mediate cell death. Recently, it was shown that Bax and Bak are also required for mitochondrial permeability transition pore (MPTP)-dependent necrosis, where, in their non-oligomeric state, they enhance permeability characteristics of the outer mitochondrial membrane. Necroptosis is another form of regulated necrosis involving the death receptors and receptor interacting protein kinases (RIP proteins, by Ripk genes). Here, we show cells or mice deficient for Bax/Bak or cyclophilin D, a protein that regulates MPTP opening, are resistant to cell death induced by necroptotic mediators. We show that Bax/Bak oligomerization is required for necroptotic cell death and that this oligomerization reinforces MPTP opening. Mechanistically, we observe mixed lineage kinase domain-like (MLKL) protein and cofilin-1 translocation to the mitochondria following necroptosis induction, while expression of the mitochondrial matrix isoform of the antiapoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), is significantly reduced. Some of these effects are lost with necroptosis inhibition in Bax/Bak1 double null, Ppif(-/-), or Ripk3(-/-) fibroblasts. Hence, downstream mechanisms of cell death induced by necroptotic stimuli utilize both Bax/Bak to generate apoptotic pores in the outer mitochondrial membrane as well as MPTP opening in association with known mitochondrial death modifying proteins. Public Library of Science 2015-06-10 /pmc/articles/PMC4465034/ /pubmed/26061004 http://dx.doi.org/10.1371/journal.pone.0130520 Text en © 2015 Karch et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Karch, Jason Kanisicak, Onur Brody, Matthew J. Sargent, Michelle A. Michael, Demetria M. Molkentin, Jeffery D. Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death |
title | Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death |
title_full | Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death |
title_fullStr | Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death |
title_full_unstemmed | Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death |
title_short | Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death |
title_sort | necroptosis interfaces with momp and the mptp in mediating cell death |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465034/ https://www.ncbi.nlm.nih.gov/pubmed/26061004 http://dx.doi.org/10.1371/journal.pone.0130520 |
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