Protosappanin A Maintains Neuronal Mitochondrial Homeostasis through Promoting Autophagic Degradation of Bax,ACS Chemical Neuroscience

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Protosappanin A Maintains Neuronal Mitochondrial Homeostasis through Promoting Autophagic Degradation of Bax
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-11-23 , DOI: 10.1021/acschemneuro.0c00488
Li-Xi Liao ₁ , Jing-Kang Wang ₁ , Yan-Jun Wan ₁ , Yang Liu ₁ , Xin Dong ₁ , Peng-Fei Tu ₁ , Ke-Wu Zeng ₁

Affiliation

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.

中文翻译：

Prossappanin A通过促进Bax自噬降解来维持神经元线粒体稳态。

脑缺血伴有线粒体完整性破坏。因此，线粒体损伤的逆转在脑缺血治疗中具有巨大的潜力。作为重要的Bcl-2家族成员，促凋亡的Bax蛋白是线粒体通透性的主要效应物，并且在线粒体体内稳态中起重要作用。但是，仍然缺乏通过选择性靶向Bax的有效脑保护策略。在这项研究中，我们报道了天然小分子原黏附素A（PTA）通过增加ATP的产生并维持线粒体DNA（mtDNA）对氧-葡萄糖剥夺/再灌注（OGD / R）诱导的PC12细胞损伤显示出明显的线粒体保护作用。内容。机制研究表明，PTA选择性诱导促凋亡蛋白Bax降解，而不会影响其他Bcl-2家族成员，例如Bcl-2，Bcl-xl，Bad，Puma，Bid，Bim和Bik。此外，我们发现PTA通过自噬依赖性方式（而不是泛素-蛋白酶体途径）促进自噬标记物LC3B与Bax的降解相关联。总的来说，我们的发现提供了通过诱导Bax自噬降解来维持线粒体功能的新药理学策略，并且还提供了针对缺血性神经元损伤的新型药物候选物。

更新日期：2020-12-16

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