Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065, and.
Department of Neurology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, People's Republic of China.
J Neurosci. 2020 Apr 15;40(16):3142-3151. doi: 10.1523/JNEUROSCI.1804-19.2020. Epub 2020 Mar 9.
Prohibitin (PHB) is a critical protein involved in many cellular activities. In brain, PHB resides in mitochondria, where it forms a large protein complex with PHB2 in the inner TFmembrane, which serves as a scaffolding platform for proteins involved in mitochondrial structural and functional integrity. PHB overexpression at moderate levels provides neuroprotection in experimental brain injury models. In addition, PHB expression is involved in ischemic preconditioning, as its expression is enhanced in preconditioning paradigms. However, the mechanisms of PHB functional regulation are still unknown. Observations that nitric oxide (NO) plays a key role in ischemia preconditioning compelled us to postulate that the neuroprotective effect of PHB could be regulated by NO. Here, we test this hypothesis in a neuronal model of ischemia-reperfusion injury and show that NO and PHB are mutually required for neuronal resilience against oxygen and glucose deprivation stress. Further, we demonstrate that NO post-translationally modifies PHB through protein S-nitrosylation and regulates PHB neuroprotective function, in a nitric oxide synthase-dependent manner. These results uncover the mechanisms of a previously unrecognized form of molecular regulation of PHB that underlies its neuroprotective function. Prohibitin (PHB) is a critical mitochondrial protein that exerts a potent neuroprotective effect when mildly upregulated in mice. However, how the neuroprotective function of PHB is regulated is still unknown. Here, we demonstrate a novel regulatory mechanism for PHB that involves nitric oxide (NO) and shows that PHB and NO interact directly, resulting in protein S-nitrosylation on residue Cys of PHB. We further show that nitrosylation of PHB may be essential for its ability to preserve neuronal viability under hypoxic stress. Thus, our study reveals a previously unknown mechanism of functional regulation of PHB that has potential therapeutic implications for neurologic disorders.
抑制素 (PHB) 是一种参与多种细胞活动的关键蛋白。在大脑中，PHB 存在于线粒体中，在那里它与 PHB2 在内膜 TF 中形成一个大型蛋白质复合物，作为涉及线粒体结构和功能完整性的蛋白质的支架平台。适度水平的 PHB 过表达可在实验性脑损伤模型中提供神经保护作用。此外，PHB 表达参与缺血预处理，因为其在预处理模型中的表达增强。然而，PHB 功能调节的机制仍然未知。观察到一氧化氮 (NO) 在缺血预处理中起关键作用，这促使我们假设 PHB 的神经保护作用可以受到 NO 的调节。在这里，我们在神经元缺血再灌注损伤模型中测试了这一假设，并表明 NO 和 PHB 是神经元对缺氧和葡萄糖剥夺应激的弹性所必需的。此外，我们证明，NO 通过蛋白质 S-亚硝基化对 PHB 进行翻译后修饰，并以一氧化氮合酶依赖的方式调节 PHB 的神经保护功能。这些结果揭示了 PHB 神经保护功能的一种以前未被认识的分子调节形式的机制。
抑制素 (PHB) 是一种关键的线粒体蛋白，当在小鼠中轻度上调时，可发挥强大的神经保护作用。然而，PHB 的神经保护功能是如何调节的仍然未知。在这里，我们展示了 PHB 的一种新的调节机制，该机制涉及一氧化氮 (NO)，并表明 PHB 和 NO 直接相互作用，导致 PHB 上残基 Cys 的蛋白质 S-亚硝基化。我们进一步表明，PHB 的亚硝基化可能对其在缺氧应激下维持神经元活力的能力至关重要。因此，我们的研究揭示了 PHB 功能调节的一个以前未知的机制，这对神经疾病具有潜在的治疗意义。
