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

被引:35
作者
Patel, Pooja [1 ,2 ]
Mendoza, Arielys [1 ,2 ]
Robichaux, Dexter J. [1 ,2 ]
Wang, Meng C. [3 ,4 ,5 ]
Wehrens, Xander H. T. [1 ,2 ]
Karch, Jason [1 ,2 ]
机构
[1] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA
[2] Baylor Coll Med, Cardiovasc Res Inst, Houston, TX 77030 USA
[3] Baylor Coll Med, Huffington Ctr Aging, Dept Mol & Human Genet, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[5] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
mitochondria; permeability transition; BCL-2; family; BH3; mimetics; necrosis; mitochondrial dysfunction; calcium; ADENINE-NUCLEOTIDE TRANSLOCASE; CYCLOPHILIN-D; ADP/ATP CARRIER; ATP SYNTHASE; CELL-DEATH; CHANNEL; PROTEINS; BINDING; ADP;
D O I
10.3389/fcell.2021.765973
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:12
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