Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak

Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mito...

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Autores principales:	Pooja Patel, Arielys Mendoza, Dexter J. Robichaux, Meng C. Wang, Xander H. T. Wehrens, Jason Karch
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	mitochondria permeability transition BCL-2 family BH3 mimetics necrosis mitochondrial dysfunction Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d0aa832a997846169e462d49c336ea7a
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spelling	oai:doaj.org-article:d0aa832a997846169e462d49c336ea7a2021-12-02T00:30:37ZInhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak2296-634X10.3389/fcell.2021.765973https://doaj.org/article/d0aa832a997846169e462d49c336ea7a2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.765973/fullhttps://doaj.org/toc/2296-634XMitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.Pooja PatelPooja PatelArielys MendozaArielys MendozaDexter J. RobichauxDexter J. RobichauxMeng C. WangMeng C. WangMeng C. WangXander H. T. WehrensXander H. T. WehrensJason KarchJason KarchFrontiers Media S.A.articlemitochondriapermeability transitionBCL-2 familyBH3 mimeticsnecrosismitochondrial dysfunctionBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mitochondria permeability transition BCL-2 family BH3 mimetics necrosis mitochondrial dysfunction Biology (General) QH301-705.5
spellingShingle	mitochondria permeability transition BCL-2 family BH3 mimetics necrosis mitochondrial dysfunction Biology (General) QH301-705.5 Pooja Patel Pooja Patel Arielys Mendoza Arielys Mendoza Dexter J. Robichaux Dexter J. Robichaux Meng C. Wang Meng C. Wang Meng C. Wang Xander H. T. Wehrens Xander H. T. Wehrens Jason Karch Jason Karch Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak
description	Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.
format	article
author	Pooja Patel Pooja Patel Arielys Mendoza Arielys Mendoza Dexter J. Robichaux Dexter J. Robichaux Meng C. Wang Meng C. Wang Meng C. Wang Xander H. T. Wehrens Xander H. T. Wehrens Jason Karch Jason Karch
author_facet	Pooja Patel Pooja Patel Arielys Mendoza Arielys Mendoza Dexter J. Robichaux Dexter J. Robichaux Meng C. Wang Meng C. Wang Meng C. Wang Xander H. T. Wehrens Xander H. T. Wehrens Jason Karch Jason Karch
author_sort	Pooja Patel
title	Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak
title_short	Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak
title_full	Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak
title_fullStr	Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak
title_full_unstemmed	Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak
title_sort	inhibition of the anti-apoptotic bcl-2 family by bh3 mimetics sensitize the mitochondrial permeability transition pore through bax and bak
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/d0aa832a997846169e462d49c336ea7a
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Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak

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