The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

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 co...

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Main Authors:	Savino, Costanza, Pelicci, PierGiuseppe, Giorgio, Marco
Format:	Online
Language:	English
Published:	Hindawi Publishing Corporation 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671270/

id	pubmed-3671270
recordtype	oai_dc
spelling	pubmed-36712702013-06-13 The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration Savino, Costanza Pelicci, PierGiuseppe Giorgio, Marco Research Article 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 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. Hindawi Publishing Corporation 2013 2013-05-15 /pmc/articles/PMC3671270/ /pubmed/23766859 http://dx.doi.org/10.1155/2013/719407 Text en Copyright © 2013 Costanza Savino et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Savino, Costanza Pelicci, PierGiuseppe Giorgio, Marco
spellingShingle	Savino, Costanza Pelicci, PierGiuseppe Giorgio, Marco The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration
author_facet	Savino, Costanza Pelicci, PierGiuseppe Giorgio, Marco
author_sort	Savino, Costanza
title	The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration
title_short	The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration
title_full	The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration
title_fullStr	The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration
title_full_unstemmed	The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration
title_sort	p66shc/mitochondrial permeability transition pore pathway determines neurodegeneration
description	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 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.
publisher	Hindawi Publishing Corporation
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671270/
_version_	1611983252779696128

The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

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