A fragment of adhesion molecule L1 is imported into mitochondria, and regulates mitochondrial metabolism and trafficking

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.