Mitochondrial changes within axons in multiple sclerosis (original) (raw)

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Don J. Mahad ,

11 The Mitochondrial Research Group, Newcastle University, UK

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Iryna Ziabreva ,

11 The Mitochondrial Research Group, Newcastle University, UK

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Graham Campbell ,

11 The Mitochondrial Research Group, Newcastle University, UK

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Nichola Lax ,

11 The Mitochondrial Research Group, Newcastle University, UK

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Katherine White ,

22 EM Research Services, Newcastle University, UK

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Peter S. Hanson ,

33 Medical Toxicology Centre, Wolfson Unit, Newcastle University, UK

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Hans Lassmann ,

44 Center for Brain Research, Medical University of Vienna, Austria

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Douglass M. Turnbull

11 The Mitochondrial Research Group, Newcastle University, UK

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Received:

15 November 2008

Revision received:

16 January 2009

Accepted:

22 January 2009

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Don J. Mahad, Iryna Ziabreva, Graham Campbell, Nichola Lax, Katherine White, Peter S. Hanson, Hans Lassmann, Douglass M. Turnbull, Mitochondrial changes within axons in multiple sclerosis, Brain, Volume 132, Issue 5, May 2009, Pages 1161–1174, https://doi.org/10.1093/brain/awp046
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Abstract

Multiple sclerosis is the most common cause of non-traumatic neurological impairment in young adults. An energy deficient state has been implicated in the degeneration of axons, the pathological correlate of disease progression, in multiple sclerosis. Mitochondria are the most efficient producers of energy and play an important role in calcium homeostasis. We analysed the density and function of mitochondria using immunohistochemistry and histochemistry, respectively, in chronic active and inactive lesions in progressive multiple sclerosis. As shown before in acute pattern III and Balo's lesions, the mitochondrial respiratory chain complex IV activity is reduced despite the presence of mitochondria in demyelinated axons with amyloid precursor protein accumulation, which are predominantly located at the active edge of chronic active lesions. Furthermore, the strong non-phosphorylated neurofilament (SMI32) reactivity was associated with a significant reduction in complex IV activity and mitochondria within demyelinated axons. The complex IV defect associated with axonal injury may be mediated by soluble products of innate immunity, as suggested by an inverse correlation between complex IV activity and macrophage/microglial density in chronic lesions. However, in inactive areas of chronic multiple sclerosis lesions the mitochondrial respiratory chain complex IV activity and mitochondrial mass, judged by porin immunoreactivity, are increased within approximately half of large (>2.5 μm diameter) chronically demyelinated axons compared with large myelinated axons in the brain and spinal cord. The axon-specific mitochondrial docking protein (syntaphilin) and phosphorylated neurofilament-H were increased in chronic lesions. The lack of complex IV activity in a proportion of Na+/K+ ATPase α-1 positive demyelinated axons supports axonal dysfunction as a contributor to neurological impairment and disease progression. Furthermore, in vitro studies show that inhibition of complex IV augments glutamate-mediated axonal injury (amyloid precursor protein and SMI32 reactivity). Our findings have important implications for both axonal degeneration and dysfunction during the progressive stage of multiple sclerosis.

© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]

Topic:

• mitochondria
• amyloid beta-protein precursor
• axon
• histocytochemistry
• multiple sclerosis
• myelin sheath
• porin
• brain
• spinal cord
• respiratory chain

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