Tuesday, 17 March 2015

Mitochondrial dysfunction linked to neurodegeneration in MS

Chicken or egg? Does mitochondrial dysfunction cause neurodegeneration or does neurodegeneration cause mitochondrial dysfunction? #MSBlog #MSResearch

"Energetics; the new buzz word in MS. There is mounting evidence that malfunction of mitochondria contributes to neurodegeneration in MS. The mitochondria are the energy factories of the cells and generate much needed energy for nerve conduction and to maintain the integrity of axons and neurons. In addition, mitochondria have the ability to signal to the cell to commit suicide. When mitochondria are not working very well the cell has to generate energy without using oxygen. This results in the production of lactic acid. The study below shows that lactic acid detected in the peripheral blood of MSers correlates with neurodegeneration in the retina. The investigators imply in their conclusions that this may be causal, i.e. the mitochondrial dysfunction may be causing the neurodegeneration. Playing devil's advocate it may be the other way round; could neurodegeneration be causing mitochondrial dysfunction? As cells die they trigger local innate immune reactions via complex cell sensing mechanisms. Some of these mechanisms produce mediators that then lead to secondary mitochondrial dysfunction. This is called reverse causation. To dissect out these two hypotheses we need to treat MS with drugs that enhance mitochondrial function or protect them and see if it improves MS and/or delays MS disease progression. In fact we have included a novel drug class in our recent funding application to the progressive MS alliance."


Epub: Petzold et al. Visual pathway neurodegeneration winged by mitochondrial dysfunction. Ann Clin Transl Neurol. 2015;2(2):140-50. doi: 10.1002/acn3.157.

OBJECTIVES: To test for structural and functional contribution of mitochondrial dysfunction to neurodegeneration in multiple sclerosis (MS). A visual pathway model void of MS lesions was chosen in order to exclude neurodegeneration secondary to lesion related axonotmesis.

METHODS: A single-centre cohort study (230 MS patients, 63 controls). Spectral domain optical coherence tomography of the retina, 3T magnetic resonance imaging of the brain, spectrophotometric assessment of serum lactate levels. Postmortem immunohistochemistry.

RESULTS: The visual pathway was void of MS lesions in 31 patients and 31 age-matched controls. Serum lactate was higher in MS compared to controls (P = 0.029). High serum lactate was structurally related to atrophy of the retinal nerve fiber layer at the optic disc (P = 0.041), macula (P = 0.025), and the macular ganglion cell complex (P = 0.041). High serum lactate was functionally related to poor color vision (P < 0.01), Expanded Disability Status Scale score (R = 0.37, P = 0.041), Guy's Neurological disability score (R = 0.38, P = 0.037), MS walking scale (R = 0.50, P = 0.009), upper limb motor function (R = 0.53, P = 0.002). Immunohistochemistry demonstrated increased astrocytic expression of a key lactate generating enzyme in MS lesions as well as profound vascular expression of monocarboxylate transporter-1, which is involved in lactate transport.

INTERPRETATION: This study provides structural, functional, and translational evidence for visual pathway neurodegeneration in MS related to mitochondrial dysfunction.

8 comments:

  1. Wouldn't most of the lactate be coming from the muscles?

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    1. Probably not at rest, when samples are taken?

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  2. I suspect neurodegeneration causes mitochondrial dysfunction. If mitochondrial dysfunction was the primary cause why would MS be a disease of adults? I think it would show itself in children if it was a cause.

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    1. I agree that the mitochondrial dysfunction is as a result of neuronal stress as a result of inflammation. More on this to come on the blog and the upcoming research day.

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  3. What do you guys think of MitoQ in this case which is seen as helping mitochondria?
    I know it's been shown in a study in the mouse model EAE to be helpful but I imagine no pharma has any interest in this due to no ability to make money?

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    1. It is sold as a beauty product to stop wrinkles

      It was shown to be an immune modulator in EAE at 200 to 4000 times the human dose

      Water at 5 times the recommended dose stops EAE.

      Helping mitochondria can stop neurodegeneration as you will see soon....

      Will MItioQ be developed for MS, do the right EAE experiments first and you may get the answer,but I suspect you have the answer already

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  4. What do you think of supplementing with this I know of a lot of reviews from people who claim it's helped them? I think its 10mg a day

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    Replies
    1. As I consistently say until there is evidence I will not be recommending anything.

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