Mitochondria as Crucial Players in Demyelinated Axons: Lessons from Neuropathology and Experimental Demyelination

Figure 1

Mitochondrial changes within axons in response to demyelination and further cytoskeletal injury. Sodium channels (Na_v1.6) are located at nodes of Ranvier in the CNS whilst the Na⁺/K⁺ ATPase extends the myelinated segments (internodes). To facilitate the extended energy demand of the axon, mitochondria have been shown to distribute throughout the axonal cytoplasm in small axons in the CNS (green). The redistribution of sodium channels facilitates the continuation of action potentials along the demyelinated axons (blue). Mitochondrial dysfunction can leave the axon vulnerable as observed in acute and chronic stages of MS (red). It is hypothesised that the failure of the Na⁺/K⁺ ATPase, possibly due to mitochondrial dysfunction, can lead to increased sodium concentrations in the axoplasm. Reversal of the Na⁺/Ca²⁺ exchanger can ensue, resulting in toxic calcium levels and downstream processes with consequent axonal degeneration. Mitochondrial dysfunction (red) possibly by inflammatory products such as nitric oxide (NO) and peroxynitrite (ONOO⁻) can lead to membrane depolarisation and retrograde transport toward the neuronal soma (arrow to the left). A population of axons have been shown to exist without the Na⁺/K⁺ ATPase which would also have a similar effect to an energy defect.