Soldatov Vladislav, Venediktov Artem, Belykh Andrei, Piavchenko Gennadii, Naimzada Mukhammad David, Ogneva Nastasya, Kartashkina Natalia, Bushueva Olga
Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia.
Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
Front Mol Neurosci. 2024 Dec 11;17:1513084. doi: 10.3389/fnmol.2024.1513084. eCollection 2024.
As many proteins prioritize functionality over constancy of structure, a proteome is the shortest stave in the Liebig's barrel of cell sustainability. In this regard, both prokaryotes and eukaryotes possess abundant machinery supporting the quality of the proteome in healthy and stressful conditions. This machinery, namely chaperones, assists in folding, refolding, and the utilization of client proteins. The functions of chaperones are especially important for brain cells, which are highly sophisticated in terms of structural and functional organization. Molecular chaperones are known to exert beneficial effects in many brain diseases including one of the most threatening and widespread brain pathologies, ischemic stroke. However, whether and how they exert the antioxidant defense in stroke remains unclear. Herein, we discuss the chaperones shown to fight oxidative stress and the mechanisms of their antioxidant action. In ischemic stroke, during intense production of free radicals, molecular chaperones preserve the proteome by interacting with oxidized proteins, regulating imbalanced mitochondrial function, and directly fighting oxidative stress. For instance, cells recruit Hsp60 and Hsp70 to provide proper folding of newly synthesized proteins-these factors are required for early ischemic response and to refold damaged polypeptides. Additionally, Hsp70 upregulates some dedicated antioxidant pathways such as FOXO3 signaling. Small HSPs decrease oxidative stress via attenuation of mitochondrial function through their involvement in the regulation of Nrf- (Hsp22), Akt and Hippo (Hsp27) signaling pathways as well as mitophagy (Hsp27, Hsp22). A similar function has also been proposed for the Sigma-1 receptor, contributing to the regulation of mitochondrial function. Some chaperones can prevent excessive formation of reactive oxygen species whereas Hsp90 is suggested to be responsible for pro-oxidant effects in ischemic stroke. Finally, heat-resistant obscure proteins (Hero) are able to shield client proteins, thus preventing their possible over oxidation.
由于许多蛋白质更注重功能而非结构的稳定性，蛋白质组是细胞可持续性的利比希氏桶中最短的木板。在这方面，原核生物和真核生物都拥有丰富的机制，在健康和应激条件下支持蛋白质组的质量。这种机制，即分子伴侣，协助客户蛋白质的折叠、重新折叠和利用。分子伴侣的功能对脑细胞尤为重要，脑细胞在结构和功能组织方面高度复杂。已知分子伴侣在许多脑部疾病中发挥有益作用，包括最具威胁性和广泛存在的脑部疾病之一——缺血性中风。然而，它们在中风中是否以及如何发挥抗氧化防御作用仍不清楚。在此，我们讨论已被证明能对抗氧化应激的分子伴侣及其抗氧化作用机制。在缺血性中风中，在自由基大量产生期间，分子伴侣通过与氧化蛋白质相互作用、调节失衡的线粒体功能以及直接对抗氧化应激来维持蛋白质组。例如，细胞募集Hsp60和Hsp70以确保新合成蛋白质的正确折叠——这些因子是早期缺血反应和重新折叠受损多肽所必需的。此外，Hsp70上调一些专门的抗氧化途径，如FOXO3信号通路。小热休克蛋白通过参与Nrf - （Hsp22）、Akt和Hippo（Hsp27）信号通路以及线粒体自噬（Hsp27、Hsp22）来调节线粒体功能，从而降低氧化应激。已有人提出西格玛 - 1受体也有类似功能，有助于线粒体功能的调节。一些分子伴侣可以防止活性氧的过度形成，而Hsp90被认为在缺血性中风中具有促氧化作用。最后，耐热性不明蛋白（Hero）能够保护客户蛋白质，从而防止其可能的过度氧化。
