Mitochondrial Dynamics, Localization, and Bioenergetics Regulated by Netrin-1 in Oligodendrocytes

Abstract

Mitochondria produce energy and molecular precursors essential for myelin synthesis by oligodendrocytes. In multiple sclerosis, mitochondria become dysfunctional leaving oligodendrocytes more susceptible to oxidative damage than neurons. Despite such unique characteristics, no studies have examined the signaling pathways that regulate mitochondrial dynamics in oligodendrocytes. We show that mitochondria traverse compacted myelin-like membranes by squeezing through thin cytoplasmic channels half their own diameter and are present within paranodal loops in mature myelin. We investigated if extracellular netrin-1, which maintains paranodal organization, influences mitochondrial localization and function. An unbiased proteomic screen, super-resolution microscopy, and live-cell imaging identified rapid local recruitment of mitochondria and paranodal proteins to netrin-1-coated microbeads. Netrin-1-dependent Src-family kinase activation and ROCK inhibition induced mitochondrial elongation, hyperpolarization of inner membrane potential, and enhanced glycolysis. Our findings identify a critical signaling mechanism that regulates mitochondrial dynamics, localization, and function in myelin.