Rottenberg Hagai
New Hope Biomedical R&D, 23 W. Bridge Street, 18938, New Hope, PA, USA.
J Bioenerg Biomembr. 2023 Feb;55(1):15-31. doi: 10.1007/s10863-023-09957-8. Epub 2023 Feb 4.
The mitochondrial bc1 complex is a major source of mitochondrial superoxide. While bc1-generated superoxide plays a beneficial signaling role, excess production of superoxide lead to aging and degenerative diseases. The catalytic core of bc1 comprises three peptides -cytochrome b, Fe-S protein, and cytochrome c1. All three core peptides exhibit accelerated evolution in anthropoid primates. It has been suggested that the evolution of cytochrome b in anthropoids was driven by a pressure to reduce the production of superoxide. In humans, the bc1 core peptides exhibit anthropoid-specific substitutions that are clustered near functionally critical sites that may affect the production of superoxide. Here we compare the high-resolution structures of bovine, mouse, sheep and human bc1 to identify structural changes that are associated with human-specific substitutions. Several cytochrome b substitutions in humans alter its interactions with other subunits. Most significantly, there is a cluster of seven substitutions, in cytochrome b, the Fe-S protein, and cytochrome c1 that affect the interactions between these proteins at the tether arm of the Fe-S protein and may alter the rate of ubiquinone oxidation and the rate of superoxide production. Another cluster of substitutions near heme bH and the ubiquinone reduction site, Qi, may affect the rate of ubiquinone reduction and thus alter the rate of superoxide production. These results are compatible with the hypothesis that cytochrome b in humans (and other anthropoid primates) evolve to reduce the rate of production of superoxide thus enabling the exceptional longevity and exceptional cognitive ability of humans.
线粒体bc1复合物是线粒体超氧化物的主要来源。虽然bc1产生的超氧化物发挥有益的信号传导作用，但超氧化物的过量产生会导致衰老和退行性疾病。bc1的催化核心由三种肽组成——细胞色素b、铁硫蛋白和细胞色素c1。所有这三种核心肽在类人猿灵长类动物中都表现出加速进化。有人提出，类人猿中细胞色素b的进化是由降低超氧化物产生的压力驱动的。在人类中，bc1核心肽表现出类人猿特有的替代，这些替代聚集在可能影响超氧化物产生的功能关键位点附近。在这里，我们比较了牛、小鼠、绵羊和人类bc1的高分辨率结构，以确定与人类特有的替代相关的结构变化。人类中细胞色素b的几种替代改变了它与其他亚基的相互作用。最显著的是，在细胞色素b、铁硫蛋白和细胞色素c1中有一组七个替代，它们影响这些蛋白质在铁硫蛋白的系链臂处的相互作用，并可能改变泛醌氧化速率和超氧化物产生速率。另一组位于血红素bH和泛醌还原位点Qi附近的替代可能会影响泛醌还原速率，从而改变超氧化物产生速率。这些结果与以下假设一致，即人类（和其他类人猿灵长类动物）中的细胞色素b进化以降低超氧化物的产生速率，从而实现人类超常的寿命和超常的认知能力。
