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

Sleigh, J. N.; Mattedi, F.; Richter, S.; Ng, K.; Steinmark, I. E.; Ivanova, I.; Daraban, I. L.; Joshi, P. P.; Annuario, E.; Awale, S.; Yahioglu, G.; Mitchell, J. C.; Suhling, K.; Schiavo, G.; Vagnoni, A.

doi:10.1101/2023.09.18.558344

bioRxiv · 10.1101/2023.09.18.558344

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

Sleigh, J. N.·Mattedi, F.·Richter, S.·Ng, K.·Steinmark, I. E.·Ivanova, I.·Daraban, I. L.·Joshi, P. P.·Annuario, E.·Awale, S.·Yahioglu, G.·Mitchell, J. C.·Suhling, K.·Schiavo, G.·Vagnoni, A.

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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 neuronal cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Increasing cytoplasmic crowding in the somatic compartment of DRG neurons grown in microfluidic chambers reduces mitochondrial axonal trafficking, suggesting a mechanistic link between the regulation of cytoplasmic viscosity and mitochondrial dynamics. 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.

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Sleigh, J. N., Mattedi, F., Richter, S., Ng, K., Steinmark, I. E., Ivanova, I., Daraban, I. L., Joshi, P. P., Annuario, E., Awale, S., Yahioglu, G., Mitchell, J. C., Suhling, K., Schiavo, G., Vagnoni, A.. 2023-09-18. Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons. https://doi.org/10.1101/2023.09.18.558344

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