Hoeser Franziska, Saura Patricia, Harter Caroline, Kaila Ville R I, Friedrich Thorsten
Institut für Biochemie, Albert-Ludwigs-Universität Freiburg Germany
Department of Biochemistry and Biophysics, Stockholm University Sweden
Chem Sci. 2025 Mar 21;16(17):7374-7386. doi: 10.1039/d4sc04036h. eCollection 2025 Apr 30.
Respiratory complex I is a central enzyme of cellular energy metabolism that couples electron transfer with proton translocation across a biological membrane. In doing so, it powers oxidative phosphorylation that drives energy consuming processes. Mutations in complex I lead to severe neurodegenerative diseases in humans. However, the biochemical consequences of these mutations remain largely unknown. Here, we use the complex I as a model to biochemically characterize the F124L mutation found in patients suffering from Leigh syndrome. We show that the mutation drastically perturbs proton translocation and electron transfer activities to the same extent, despite the remarkable 140 Å distance between the mutated position and the electron transfer domain. Our molecular dynamics simulations suggest that the disease-causing mutation induces conformational changes that hamper the propagation of an electric wave through an ion-paired network essential for proton translocation. Our findings imply that malfunction of the proton translocation domain is entirely transmitted to the electron transfer domain underlining the action-at-a-distance coupling in the proton-coupled electron transfer of respiratory complex I.
呼吸链复合体I是细胞能量代谢的核心酶，它将电子传递与质子跨生物膜转运偶联起来。通过这种方式，它为驱动能量消耗过程的氧化磷酸化提供动力。复合体I中的突变会导致人类严重的神经退行性疾病。然而，这些突变的生化后果在很大程度上仍不清楚。在这里，我们以复合体I为模型，对患有Leigh综合征患者中发现的F124L突变进行生化特征分析。我们表明，尽管突变位点与电子传递结构域之间有显著的140 Å距离，但该突变在相同程度上极大地扰乱了质子转运和电子传递活性。我们的分子动力学模拟表明，致病突变会诱导构象变化，从而阻碍电波通过质子转运所必需的离子对网络进行传播。我们的研究结果表明，质子转运结构域的功能障碍会完全传递到电子传递结构域，这突出了呼吸链复合体I质子偶联电子传递中的远距离偶联作用。
