Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095.
Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2304884120. doi: 10.1073/pnas.2304884120. Epub 2023 Sep 21.
How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.
导致致盲性疾病莱伯遗传性视神经病变（LHON）的单一氨基酸突变如何损害线粒体中的电子传递？我们使用分子动力学和自由能微扰模拟工具研究了线粒体蛋白 ND1 中 m.3460G>A 突变引起的变化，目的是确定该突变影响线粒体功能的机制。最近的一项分析表明，该突变将丙氨酸 A52 替换为苏氨酸，破坏了与电子传递蛋白辅酶 Q10 结合的区域的稳定性。我们发现了两个涉及辅酶 Q10 作用的功能相反的变化。第一个表明，来自末端 Fe/S 复合物 N2 的量子电子转移到辅酶 Q10 头部基团，停靠在其结合口袋中，增强了。然而，这种积极的调整被我们的发现所掩盖，即辅酶 Q10 在氧化和还原状态下的迁移性，进入和离开其结合口袋，被突变以一种促进活性氧物种生成的方式受到干扰。LHON 突变引起的活性氧物种增加被认为是导致这种视神经病变的原因。
