Abstract
Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.
Highlights
Demyelination leads to the damage and loss of axons and the progression of neurological disability in demyelinating disorders, including multiple sclerosis (MS) [17, 47, 70]
Mitochondria mobilise from the neuronal cell body to the axon, increasing mitochondrial content following demyelination: the axonal response of mitochondria to demyelination (ARMD)
Following photoconversion of axonal mitochondria, we identified a large increase in the number of unconverted mitochondria moving from the Purkinje cell body to the proximal axon segment upon demyelination (Fig. 1c, e–g and videos 6–10, online resource), compared to control (Fig. 1b, d, f–g and videos 1–5, online resource)
Summary
Demyelination leads to the damage and loss of axons and the progression of neurological disability in demyelinating disorders, including multiple sclerosis (MS) [17, 47, 70]. In inflammatory demyelinating disorders such as MS, axons are damaged during acute demyelination, and they can degenerate over much longer timescale due to chronic lack of myelin [70]. Myelination enables saltatory conduction of action potentials and conserves neuronal energy by clustering voltagegated Na+ channels to the nodes of Ranvier [47]. When ATP is not readily available, an excessively high sodium concentration in the axon leads to the reversal of Na+/Ca2+ exchanger and accumulation of calcium, which activates calcium dependent proteases and degeneration of the demyelinated axon [76]. One underlying mechanism that contributes to the degeneration of demyelinated axons, likely both acute and chronic, is an imbalance between the increased energy demand of nerve conduction and the generation of ATP in the demyelinated axon [37, 71]
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