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Axonopathy, Mitochondrial Abnormalities, and Disability in MS (ACTRIMS 2016)

Altered mitochondrial function in degenerating axons may play an important role in axonal and neuronal cell death suggested a presentation at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, held February 18-20 in New Orleans.

Inflammatory demyelinating disease processes in the early stages of MS, triggers a cascade of pathogenic mechanisms that lead to neurodegeneration that are amplified by brain ageing and accumulation of disease burden suggested Don Mahad, MD, University of Edinburgh, United Kingdom. One of the key elements driving neurodegeneration is the accumulation of mitochondrial damage in axons. Abnormal mitochondrial function in axons may lead to chronic cell stress, which ultimately results in axonal and neuronal cell death.

Axon loss in progressive MS is hypothesized to occur in 3 steps: formation, amplification, and aberrant placement.[1] In healthy neurons, mitochondria are mostly located in the cell body. After a somatic insult, these mitochondria relocate to the axon and participate in tissue repair and cell maintenance. However, in the presence of ongoing inflammation this mechanism may be exhausted. Mitochondria lose their ability to generate cytochrome C oxidase and participate in the respiratory chain over time. The longer this condition lasts, the more mitochondrial reorganization to the axon occurs. Preclinical models have confirmed this hypothesis. After experimental demyelination, demyelinated axons contain more mitochondria that are larger and functionally intact.

Mitochondrial changes are established in patients with MS. Some of these changes include mitochondrial respiratory chain enzyme deficiencies, which compromise ATP production capacity. In patients with progressive MS, there is a downregulation in the mitochondrial respiratory chain complex IV activity in demyelinated axons. Both healthy neurons and intact neurons show complex IV activity, but degenerating neurons do not. This decreased capacity to produce ATP in the neuronal cell bodies is combined with an increased energy demand in demyelinated axons.

It is difficult to reproduce oxidative tissue injury in preclinical models. To combat this, Dr. Mahad has developed a method to model neuronal mitochondrial abnormalities using a transgenic mouse model (COX10Thy1-CreERT2) with neuronal mitochondrial defects. Using this model, abnormal mitochondria can be visualized in demyelinated axons. Additionally, these mice show motor fatigability 6 weeks after demyelination, an effect that is amplified with age. This is an interesting behavioral outcome that is comparative to human patients with progressive MS.

Dr. Mahad concluded that this new preclinical model will allow research into certain aspects of progressive MS, and also allow preclinical testing of therapeutic agents.


Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015 Feb;14(2):183-93.

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About the Editors

  • Prof Timothy Vartanian

    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
  • Dr Rebecca Farber

    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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