Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Vector Core Unit, Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
J Cell Sci. 2018 May 8;131(9):jcs210500. doi: 10.1242/jcs.210500.
The cell adhesion molecule L1 (also known as L1CAM) plays important roles in the mammalian nervous system under physiological and pathological conditions. We have previously reported that proteolytic cleavage of L1 by myelin basic protein leads to the generation of a 70 kDa transmembrane L1 fragment (L1-70) that promotes neuronal migration and neuritogenesis. Here, we provide evidence that L1-70 is imported from the cytoplasm into mitochondria. Genetic ablation of L1, inhibition of mitochondrial import of L1-70 or prevention of myelin basic protein-mediated generation of L1-70 all lead to reduced mitochondrial complex I activity, and impaired mitochondrial membrane potential, fusion, fission and motility, as well as increased retrograde transport. We identified NADH dehydrogenase ubiquinone flavoprotein 2 as a binding partner for L1, suggesting that L1-70 interacts with this complex I subunit to regulate complex I activity. The results of our study provide insights into novel functions of L1 in mitochondrial metabolism and cellular dynamics. These functions are likely to ameliorate the consequences of acute nervous system injuries and chronic neurodegenerative diseases.
细胞黏附分子 L1（也称为 L1CAM）在生理和病理条件下对哺乳动物神经系统发挥重要作用。我们之前曾报道过，髓鞘碱性蛋白对 L1 的蛋白水解切割会产生一个 70 kDa 的跨膜 L1 片段（L1-70），从而促进神经元迁移和突起生成。在这里，我们提供的证据表明，L1-70 从细胞质被导入线粒体。L1 的基因缺失、L1-70 进入线粒体的抑制或髓鞘碱性蛋白介导的 L1-70 生成的预防，均会导致线粒体复合物 I 活性降低、线粒体膜电位受损、融合、分裂和运动，以及逆行运输增加。我们鉴定出烟酰胺腺嘌呤二核苷酸脱氢酶泛醌黄素蛋白 2 是 L1 的结合伴侣，这表明 L1-70 与该复合物 I 亚基相互作用，以调节复合物 I 的活性。我们研究的结果为 L1 在线粒体代谢和细胞动力学中的新功能提供了深入了解。这些功能可能会减轻急性神经系统损伤和慢性神经退行性疾病的后果。
