State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
ACS Chem Neurosci. 2020 Dec 16;11(24):4223-4230. doi: 10.1021/acschemneuro.0c00488. Epub 2020 Nov 23.
Cerebral ischemia is accompanied by mitochondrial integrity destruction. Thus, reversion of mitochondrial damage holds great potential for cerebral ischemia therapy. As a crucial Bcl-2 family member, pro-apoptotic Bax protein is a main effector of mitochondrial permeabilization and plays an important role in mitochondrial homeostasis. However, there is still a lack of an effective cerebral protective strategy through selectively targeting Bax. In this study, we reported that natural small-molecule protosappanin A (PTA) showed a significant mitochondrial protective effect on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cells injury through increasing ATP production and maintaining mitochondrial DNA (mtDNA) content. The mechanism study revealed that PTA selectively induced pro-apoptotic protein Bax degradation, without affecting other Bcl-2 family members such as Bcl-2, Bcl-xl, Bad, Puma, Bid, Bim, and Bik. In addition, we found that PTA promoted the association of autophagosomal marker LC3B to Bax for its degradation via an autophagy-dependent manner but not the ubiquitin-proteasome pathway. Collectively, our findings offered a new pharmacological strategy for maintaining mitochondrial function by inducing autophagic degradation of Bax and also provided a novel drug candidate against ischemic neuronal injury.
脑缺血伴随着线粒体完整性的破坏。因此，逆转线粒体损伤对于脑缺血治疗具有巨大的潜力。作为 Bcl-2 家族的重要成员，促凋亡 Bax 蛋白是线粒体通透性转换的主要效应因子，在维持线粒体动态平衡中发挥着重要作用。然而，通过选择性靶向 Bax 来实现有效的脑保护策略仍然缺乏。在本研究中，我们报道天然小分子原七叶皂苷甲（PTA）通过增加 ATP 产生和维持线粒体 DNA（mtDNA）含量，对氧葡萄糖剥夺/复氧（OGD/R）诱导的 PC12 细胞损伤表现出显著的线粒体保护作用。机制研究表明，PTA 选择性诱导促凋亡蛋白 Bax 降解，而不影响其他 Bcl-2 家族成员，如 Bcl-2、Bcl-xl、Bad、Puma、Bid、Bim 和 Bik。此外，我们发现 PTA 通过自噬依赖性途径而不是泛素蛋白酶体途径促进自噬标记物 LC3B 与 Bax 的结合，从而促进 Bax 的降解。总之，我们的研究结果为通过诱导 Bax 的自噬降解来维持线粒体功能提供了一种新的药理学策略，并为缺血性神经元损伤提供了一种新的候选药物。
