Document Detail


Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice.
MedLine Citation:
PMID:  16478527     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mitochondrial respiratory chain dysfunction, impaired intracellular Ca2+ homeostasis and activation of the mitochondrial apoptotic pathway are pathological hallmarks in animal and cellular models of familial amyotrophic lateral sclerosis associated with Cu/Zn-superoxide dismutase mutations. Although intracellular Ca2+ homeostasis is thought to be intimately associated with mitochondrial functions, the temporal and causal correlation between mitochondrial Ca2+ uptake dysfunction and motor neuron death in familial amyotrophic lateral sclerosis remains to be established. We investigated mitochondrial Ca2+ handling in isolated brain, spinal cord and liver of mutant Cu/Zn-superoxide dismutase transgenic mice at different disease stages. In G93A mutant transgenic mice, we found a significant decrease in mitochondrial Ca2+ loading capacity in brain and spinal cord, as compared with age-matched controls, very early on in the course of the disease, long before the onset of motor weakness and massive neuronal death. Ca2+ loading capacity was not significantly changed in liver G93A mitochondria. We also confirmed Ca2+ capacity impairment in spinal cord mitochondria from a different line of mice expressing G85R mutant Cu/Zn-superoxide dismutase. In excitable cells, such as motor neurons, mitochondria play an important role in handling rapid cytosolic Ca2+ transients. Thus, mitochondrial dysfunction and Ca2+-mediated excitotoxicity are likely to be interconnected mechanisms that contribute to neuronal degeneration in familial amyotrophic lateral sclerosis.
Authors:
Maria Damiano; Anatoly A Starkov; Susanne Petri; Kathuna Kipiani; Mahmoud Kiaei; Marina Mattiazzi; M Flint Beal; Giovanni Manfredi
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  96     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-02-15     Completed Date:  2006-05-11     Revised Date:  2012-02-23    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1349-61     Citation Subset:  IM    
Affiliation:
The Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Age Factors
Animals
Brain / cytology,  metabolism
Calcium / metabolism*
Cytochromes c / metabolism
Humans
Membrane Potentials / genetics
Mice
Mice, Transgenic
Microscopy, Electron, Transmission / methods
Mitochondria / metabolism*
Mitochondrial Membranes
Motor Neuron Disease / metabolism*
Motor Neurons / cytology*
Oxygen Consumption / genetics
Respiration / genetics
Spinal Cord / cytology,  metabolism
Superoxide Dismutase / genetics*
Time Factors
Grant Support
ID/Acronym/Agency:
GFP01006//Telethon; P01 NS011766-27/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
56-65-5/Adenosine Triphosphate; 7440-70-2/Calcium; 9007-43-6/Cytochromes c; EC 1.15.1.-/SOD1 G93A protein; EC 1.15.1.1/Superoxide Dismutase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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