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.