Karch Jason, Kwong Jennifer Q, Burr Adam R, Sargent Michelle A, Elrod John W, Peixoto Pablo M, Martinez-Caballero Sonia, Osinska Hanna, Cheng Emily H-Y, Robbins Jeffrey, Kinnally Kathleen W, Molkentin Jeffery D
Department of Pediatrics , Cincinnati Children's Hospital Medical Center, University of Cincinnati , Cincinnati , United States.
Elife. 2013 Aug 27;2:e00772. doi: 10.7554/eLife.00772.
A critical event in ischemia-based cell death is the opening of the mitochondrial permeability transition pore (MPTP). However, the molecular identity of the components of the MPTP remains unknown. Here, we determined that the Bcl-2 family members Bax and Bak, which are central regulators of apoptotic cell death, are also required for mitochondrial pore-dependent necrotic cell death by facilitating outer membrane permeability of the MPTP. Loss of Bax/Bak reduced outer mitochondrial membrane permeability and conductance without altering inner membrane MPTP function, resulting in resistance to mitochondrial calcium overload and necrotic cell death. Reconstitution with mutants of Bax that cannot oligomerize and form apoptotic pores, but still enhance outer membrane permeability, permitted MPTP-dependent mitochondrial swelling and restored necrotic cell death. Our data predict that the MPTP is an inner membrane regulated process, although in the absence of Bax/Bak the outer membrane resists swelling and prevents organelle rupture to prevent cell death. DOI:http://dx.doi.org/10.7554/eLife.00772.001.
基于缺血的细胞死亡中的一个关键事件是线粒体通透性转换孔（MPTP）的开放。然而，MPTP 各组分的分子身份仍然未知。在这里，我们确定凋亡细胞死亡的核心调节因子、Bcl-2 家族成员 Bax 和 Bak，也是线粒体孔依赖性坏死性细胞死亡所必需的，它们通过促进 MPTP 的外膜通透性来实现这一点。Bax/Bak 的缺失降低了线粒体外膜的通透性和电导率，而不改变内膜 MPTP 的功能，从而导致对线粒体钙超载和坏死性细胞死亡的抗性。用不能寡聚化并形成凋亡孔但仍能增强外膜通透性的 Bax 突变体进行重构，可使 MPTP 依赖性线粒体肿胀并恢复坏死性细胞死亡。我们的数据预测，MPTP 是一个受内膜调节的过程，尽管在没有 Bax/Bak 的情况下，外膜会抵抗肿胀并防止细胞器破裂以防止细胞死亡。DOI:http://dx.doi.org/10.7554/eLife.00772.001 。
