Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo

Abstract

The importance of mitochondria for neuronal function is evident by the large number of neurodegenerative diseases that have been associated with a disruption of mitochondrial function or transport (reviewed in [1, 2]). Mitochondria are essential for proper biological function as a result of their ability to produce ATP through oxidative phosphorylation, buffer cytoplasmic calcium, regulate lipid biosynthesis, and trigger apoptosis (reviewed in [2]). Efficient transport of mitochondria is thought to be particularly important in neurons in light of their compartmentalization,length of axonal processes, and high-energy requirements (reviewed in [3]). However, the majority of these results were obtained using short-term, invitro neuronal culture models, and very little is currently known about mitochondrial dynamics in mature axons of the mammalian CNS invitro or invivo. Furthermore, recent evidence has demonstrated that mitochondrial immobilization at specific points along the axon,such as presynaptic boutons, play critical roles in axon morphogenesis [4, 5]. We report that as cortical axons mature, motility of mitochondria (but not other cargoes) is dramatically reduced and this coincides with increased localization to presynaptic sites. We also demonstrateusing photo-conversion that invitro matureaxons display surprisingly limited long-range mitochondrial transport. Finally, using invivo two-photon microscopy in anesthetized or awake-behaving mice, we document for the firsttime that mitochondrial motility is also remarkably low in distal cortical axons invivo. These results argue that mitochondrial immobilization and presynaptic localization are important hallmarks of mature CNS axons both invitro and invivo.