Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons

Abstract

Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated with reduced cellular health. However, it is still unclear to what extent the decline of mitochondrial transport and function observed during ageing are coupled, and if somal and axonal mitochondria display compartment-specific features that make them more susceptible to the ageing process. It is also not known whether the biophysical state of the cytoplasm, thought to affect many cellular functions, changes with age to impact mitochondrial trafficking and homeostasis. Focusing on the mouse peripheral nervous system, we show that age-dependent decline in mitochondrial trafficking is accompanied by reduction of mitochondrial membrane potential and intra-mitochondrial viscosity, but not calcium buffering, in both somal and axonal mitochondria. Intriguingly, we observe a specific increase in cytoplasmic viscosity in the cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Our work provides a reference for studying the relationship between neuronal mitochondrial homeostasis and the viscoelasticity of the cytoplasm in a compartment-dependent manner during ageing.

The node of Ranvier influences thein vivoaxonal transport of mitochondria and signalling endosomes

“…Axonal transport dynamics of diverse organelles at the NoR While we have previously characterised signalling endosome and mitochondrial transport in physiological and pathological conditions (Bilsland et al, 2010;Sleigh et al, 2020aSleigh et al, , 2024Tosolini et al, 2022), this is the first study to quantitatively assess in vivo axonal transport dynamics of these organelles specifically at the NoR. The transport dynamics of signalling endosomes and mitochondria across the node were similar, with both organelles displaying faster velocities at the internode, and more pausing at the NoR, which contrasts with the report of transient accelerations of neurofilaments through nodal constrictions (Walker et al, 2019).…”