Wednesday, 8 April 2015

Failure to Replicate....Mitochondria are doing something

Joshi DC, Zhang CL, Lin TM, Gusain A, Harris MG, Tree E, Yin Y, Wu C, Sheng ZH, Dempsey RJ, Fabry Z, Chiu SY. Deletion of Mitochondrial Anchoring Protects Dysmyelinating Shiverer: Implications for Progressive MS. J Neurosci. 2015;35:5293-5306.

The demyelinating disease multiple sclerosis (MS) has an early inflammatory phase followed by an incurable progressive phase with subdued inflammation and poorly understood neurodegenerative mechanism. In this study, we identified various parallelisms between progressive MS and the dysmyelinating mouse model Shiverer and then genetically deleted a major neuron-specific mitochondrial anchoring protein Syntaphilin (SNPH) from the mouse. Prevailing evidence suggests that deletion of SNPH is harmful in demyelination. Surprisingly, SNPH deletion produces striking benefits in the Shiverer by prolonging survival, reducing cerebellar damage, suppressing oxidative stress, and improving mitochondrial health. In contrast, SNPH deletion does not benefit clinical symptoms in experimental autoimmune encephalomyelitis (EAE), a model for early-phase MS. We propose that deleting mitochondrial anchoring is a novel, specific treatment for progressive MS.

The shiverer mouse does not produce myelin basic protein and dysmyelinate. This results in the mouse developing a tremor and as its name suggests it shivers. Syntaphilin, an axonal molecule that immobilizes stationary mitochondria (Energy factories of the cell) to microtubules and it has been shown previously that that syntaphilin-mediated immobilization of mitochondria to microtubules following acute demyelination and protects against axonal degeneration in the CNS. In this study the opposite appears to be the case and the shiverer mouse does better not worse. In EAE there was no effect, which is perhaps is not surprising as the amount of demyelination and nerve damage in early EAE can be minimal and the signs of EAE are often due to conduction block where the nerves don't fire property. However with completely contradictory data, would you want to take the risk? 

So now we need to wait for the next paper to see where the real result lies. But a good example to remind you not to believe every thing you read.

However the mitochondria (which are the cell's power houses) are a potential target to try and slow nerve damage. Nerves use about 20% of the bodies energy and when they are demyelinated they can be worked so hard they give up the ghost. So if you can limit how hard they work you can maybe stop nerve damage. One way is to block the mitochondrial permeability transition pore.

Sileikyte J, Roy S, Porubsky P, Neuenswander B, Wang J, Hedrick M, Pinkerton AB, Salaniwal S, Kung P, Mangravita-Novo A, Smith LH, Bourdette DN, Jackson MR, Aubé J, Chung TDY, Schoenen FJ, Forte MA, Bernardi P. Small Molecules Targeting the Mitochondrial Permeability Transition. Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.2014 Apr 15 [updated 2015 Jan 16].

It is now clear that the mitochondrial permeability transition pore (mtPTP) plays a key role in a wide variety of human diseases whose common pathology is based in mitochondrial dysfunction. Despite the facts that robust assays for the activity of the mtPTP have been established and small molecules are of obvious therapeutic importance, the identification of small molecules specifically targeting the mtPTP has not advanced. Using resources within the NIH Molecular Libraries Probe Production Centers Network (MLPCN), a number of novel small molecules that serve as inhibitors of mtPTP activation were identified and optimized. One of these compounds, the probe compound ML404 (CID 72199308) inhibits mitochondrial swelling with an EC50 = 4.9 nM, while it perturbs mitochondrial coupling (an undesired effect) at > 100 μM. This compound increases the calcium retention capacity (CRC) of mitochondria (a measure of mtPTP inhibition) 14.8-fold at 12.5 μM, a concentration that does not affect mitochondrial respiration at which the compound appears non-toxic. Compared to the prior art, the probe ML404 (CID 72199308) is the best-in-class inhibitor of the mtPTP. When the probe and analogues are used as recommended, they are “fit-for-purpose” and should be useful for advancing the search for small-molecule therapeutics for some of the most wide-spread and therapeutically challenging human diseases, such as, multiple sclerosis (MS), amyotropic lateral sclerosis (ALS), Alzheimer's disease (AD), muscular dystrophies (MDs), heart infarction, and stroke.

The Mitochondrial Permeability Transition, or MPT, is defined as an increase in the permeability of the mitochondrial membranes (to molecules of less than 1500 Daltons in molecular weight). MPT results from the opening of a mitochondrial permeability transition pore, also known as the MPT pore or MPTP. The MPT pore is a protein pore that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stroke. Induction of the permeability transition pore can lead to mitochondrial swelling and cell death and has been found to be involved in neurodegeneration,

MPT is one of the major causes of cell death in a variety of conditions. For example, it is key in neuronal cell death in excitotoxicity, in which overactivation of glutamate receptors causes excessive calcium entry into the cell. The only MPTP components identified so far are the TSPO (previously known as the peripheral benzodiazepine receptor) located in the mitochondrial outer membrane and cyclophilin-D in the mitochondrial matrix. Mice lacking the gene for cyclophilin-D have less neurodegeneration as a consequence of EAE, so a cyclophilin-D inhibitor should be neuroprotective.

In this study they made a drug that blocked the mPTP. Will it have any therapeutic value? Will it have any useful pharmacokinetics? (This determines how long a drug lasts before it is degraded)

Agents that transiently block MPT include the immune suppressant cyclosporin A. This caused significant neuroprotection in progressive MS so there is hope, but the problem is that cyclosporin A also caused kidney damage due to blockade of calcineurin, which mediates the immunosuppressive effect of cyclosporin A, which is a drug used to stop transplant rejection..However, cyclosporin A has low CNS penetration capacity so you need some thing better. Olesoxine (TRO19622) is a newly synthesised MPT blocker developed hat was tried with beta interferon (NCT01808885) and presumably failed as the trial has not reported but was finished in 2013, just as it failed in Motor neurone disease. Is this target duff?, the drug duff? or were trials not done well enough?


  1. There seems to be a lot of research and suggestiveness regarding mitochondria lately, if as we suspect the progressive types are somewhat age related and neuro degenerative then surely aiding mitochondria will help? Hence people taking coq10 MitoQ etc? There's a lot lf anecdotal reports of MitoQ being helpful, what's marketing and what's truth is hard to ascertain

  2. "Nerves use about 20% of the bodies energy and when they are demyelinated they can be worked so hard they give up the ghost. So if you can limit how hard they work you can maybe stop nerve damage."

    As far as I understand, there is no longer any caution advised in pushing to/past one's fatigue point with MS. Exercising to the point of exhaustion is not damaging, am I correct?

    1. That's a very interesting question to which I'd love to hear some of the Mouses answer cos I also do some rather exhaustive stuff and ask myself each time if I am maybe doing more harm than good.

    2. I don't will have to ask your neuro for an opinion.I am not sure there is sufficient evidence, we know exercise is good for health, becoming exhausted maybe good for the waist line as long as nerves get sufficient energy they work. but are atheletes the healthiest bunch.

    3. This relates to mitochondria in nerves not muscles. There's already been some research showing that mitochondria in nerves are more vulnerable to toxic events than mitochondria from other tissues in the body (motor neurons seem to be the most vulnerable), perhaps because they are working to capacity to maintain energy for impulse conduction. Once an axon is demyelinated, there is an over expression of sodium channels by the neuron in an attempt to maintain impulse conduction but these sodium channels are energy dependent so having a lot more of them means the drain on the mitochondria is even greater.
      So myelinated axon-no problem, demyelinated axon- heavy exercise could (and I stress could) tip the axon over the top into dying.

    4. Thank you very much both.

      I think in this case the old proverb that everything should be done in moderation is best :-)

      I also thought about sporty people maybe being protected from MS progression but there are cases of sportspeople having really bad cases of MS so I guess it's not so straightforward.

  3. Is this why people take supplements such as coq10 and MitoQ

    1. Yes it probably is but they are taking them on heresay as this is not the evidence that at the doses that they work. I am aware of an CoQ10-alike drug being trialled.


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