Thursday, 4 May 2017

Targeting mitochondria to save nerves

Luongo TS, Lambert JP, Gross P, Nwokedi M, Lombardi AA, Shanmughapriya S, Carpenter AC, Kolmetzky D, Gao E, van Berlo JH, Tsai EJ, Molkentin JD, Chen X, Madesh M, Houser SR, Elrod JW. The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature. 2017. doi: 10.1038/nature22082. [Epub ahead of print]

Mitochondrial calcium (mCa2+) has a central role in both metabolic regulation and cell death signalling. Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism for mCa2+ extrusion in excitable cells. Here we show that..deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa2+ overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa2+ efflux in cellular function and suggest that augmenting mCa2+ efflux may be a viable therapeutic strategy in disease.
What has this got to do with MS you ask? 

Calcium overload is part of the mechanism of how cells die and we saw recently that the creation of a channel between the protein synthesis and calcium-ion producing endoplasmic reticulum and the mitochondria, made the mitochondria vulnerable to failure and nerve dead. The calcium sodium exchanger in the mitochondria (powerhouses of cells) pumps in sodium and pumps out calcium. In the cell membrane it pumps in sodium and pumps out calcium, until there is too much sodium in the cell when it pulls in calcium and the cell dies. This can be blocked by blockage of the mitochondrial permeability transition pore activation. 

The Mitochondrial permeability transition pore is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as MS. Opening allows increase in the permeability of the mitochondrial membranes that can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting.

Warne J, Pryce G, Hill JM, Shi X, LennerĂ¥s F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL. Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem. 2016; 291:4356-4373.


  1. How do you see the chances for Idebenone in PPMS?

    1. Could be of use, there needs to be a trial to show some efficacy.

  2. There is a trial ongoing in NY state.

    1. I think it is Maryland as it an NIH trial.
      If you had said Coenzyme Q10 it would have rung more bells.
      It is a trial in n=88 pwPPMS due to finish in begining of 2018 and there is an extension study in n=44 to finish in 2019.

      The trial is for only 6 months and uses brain atrophy as the primary outcome. Brain atrophy is being used and surprising it is not grey mattter atrophy.

      Is brain the best place to look when so many studies point at the spinal cord, but we know spinal cord atrophy missess loads of nerve loss.

      If there is any anti-inflammatory effect then the brain on treatment may appear to shrink. If that occurs the trial is doomed.

      However I will wait until the results are reported and comment on it then

  3. funny enough lipoic acid shown to stimulate MPT yet looks like it does something very good to MS

    Stimulation of membrane permeability transition by alpha-lipoic acid and its biochemical characteristics.

    1. You want an inhibitor a stimulator of the transition pore will be bad news.

    2. I understand that, but

  4. Wow! Needless to say I only really understand the very fringe of this but to be drilling down to the mechanisms *within* mitochondria gives me an inordinate thrill.
    Thank you all

  5. Would Creatine have any blocking action on the activation of mitochondrial permeability transition pores?
    What about Coenzyme Q-10 and Cysteine?


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