Document Detail

Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels.
MedLine Citation:
PMID:  19047048     Owner:  NLM     Status:  MEDLINE    
We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an approximately 50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases.
Anna Maria Porcelli; Alessia Angelin; Anna Ghelli; Elisa Mariani; Andrea Martinuzzi; Valerio Carelli; Valeria Petronilli; Paolo Bernardi; Michela Rugolo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-12-01
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-19     Completed Date:  2009-03-23     Revised Date:  2011-11-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2045-52     Citation Subset:  IM    
Department of Evolutionary and Experimental Biology, University of Bologna, 40126 Bologna, Italy.
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MeSH Terms
Adenosine Triphosphate / biosynthesis
Biological Transport
Cell Line
Culture Media, Conditioned
DNA, Mitochondrial / genetics*
Electron Transport Complex I / genetics,  metabolism*
Galactose / metabolism
Glucose / metabolism
Mitochondria / drug effects,  genetics,  metabolism
Mitochondrial Membranes
Mutation / genetics
Oligomycins / pharmacology
Oxygen Consumption
Proto-Oncogene Proteins c-bcl-2 / metabolism
Grant Support
Reg. No./Substance:
0/Culture Media, Conditioned; 0/DNA, Mitochondrial; 0/Oligomycins; 0/Proto-Oncogene Proteins c-bcl-2; 26566-61-0/Galactose; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; EC Transport Complex I

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