Emily, M. F.; Guillaud, L.; De la Fuente Ruiz, S.; Agrawal, R.; Boerner, S.; Akimoto, Y.; Turkki, T. H.; Rosti, M. E.; Terenzio, M.

Mitochondria are trafficked along axons and provide the energy required for several intracellular mechanisms including molecular transport and local translation, which is believed to contribute to the homeostasis of the axonal compartment. Decline in mitochondria activity is one of the hallmarks of aging. It is still unclear, though, whether this decline corresponds to a concomitant reduction in the extent of axonal translation during aging. Using live cell imaging of sensory neurons, we found a significant decrease in the number of active mitochondria and the percentage of mitochondria localized to axons in aged mice compared to young mice. This decrease was mirrored by a loss of intracellular ATP as well as an ATP-dependent decrease in axoplasmic viscosity. In addition, the size of G3BP1 positive axonal granules and the number of FMRP axonal granules increased. Cumulatively, we found a functional decrease in the overall level of axonal translation in aged neurons. We were able to rescue this effect by increasing ATP synthesis, which induced a global decrease in axoplasmic viscosity, while promoting RNA granule solubilization and boosting axonal translation. Proteomic analysis of newly synthesized proteins in axons of aged vs young neurons revealed a dysregulation of pathways related to axonal biology and growth. We identified MAP1B and STAT3 as proteins whose axonal local synthesis was impaired in aged axons, and more notably show that this impairment could be rescued by increasing ATP synthesis. We believe that this research sheds light on axonal translation in aged neurons and its relationship with energy sources inside the axonal compartment, possibly presenting an opportunity for future therapeutics.