Tuesday, 18 June 2013

Blockage of mitochondrial transition pore as a route to neuroprotection

Savino C, Pelicci P, Giorgio M. The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration. Oxid Med Cell Longev. 2013;2013:719407. doi: 10.1155/2013/719407.

Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT) and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D), a key regulatory component of the PT pore (PTP) that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis(MS), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2 (Hydrogen peroxide) reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE) experiments in p66Shc knockout mice (p66Shc-/-), knock out mice for cyclophilin-D (Cyc-D-/-), and p66Shc Cyc-D double knock out (p66Shc/Cyc-D-/-) mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

Mitochondria are the powerhouses of cells and failure to produce enough energy can kill nerves. This study indicates that blockade of the mitochondria pore may be a way to treat neurogeneration....better get on this case.


  1. It seems there is a consensus emerging that the neurodegenerative aspect of MS is due to mitochondria damage. So what is in the works to prevent progression from this point of view?



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