Document Detail


Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA.
MedLine Citation:
PMID:  16402916     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations in the ATP6 gene of mtDNA (mitochondrial DNA) have been shown to cause several different neurological disorders. The product of this gene is ATPase 6, an essential component of the F1F0-ATPase. In the present study we show that the function of the F1F0-ATPase is impaired in lymphocytes from ten individuals harbouring the mtDNA T8993G point mutation associated with NARP (neuropathy, ataxia and retinitis pigmentosa) and Leigh syndrome. We show that the impaired function of both the ATP synthase and the proton transport activity of the enzyme correlates with the amount of the mtDNA that is mutated, ranging from 13-94%. The fluorescent dye RH-123 (Rhodamine-123) was used as a probe to determine whether or not passive proton flux (i.e. from the intermembrane space to the matrix) is affected by the mutation. Under state 3 respiratory conditions, a slight difference in RH-123 fluorescence quenching kinetics was observed between mutant and control mitochondria that suggests a marginally lower F0 proton flux capacity in cells from patients. Moreover, independent of the cellular mutant load the specific inhibitor oligomycin induced a marked enhancement of the RH-123 quenching rate, which is associated with a block in proton conductivity through F0 [Linnett and Beechey (1979) Inhibitors of the ATP synthethase system. Methods Enzymol. 55, 472-518]. Overall, the results rule out the previously proposed proton block as the basis of the pathogenicity of the mtDNA T8993G mutation. Since the ATP synthesis rate was decreased by 70% in NARP patients compared with controls, we suggest that the T8993G mutation affects the coupling between proton translocation through F0 and ATP synthesis on F1. We discuss our findings in view of the current knowledge regarding the rotary mechanism of catalysis of the enzyme.
Authors:
Gianluca Sgarbi; Alessandra Baracca; Giorgio Lenaz; Lucia M Valentino; Valerio Carelli; Giancarlo Solaini
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  395     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-04-06     Completed Date:  2006-05-10     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  493-500     Citation Subset:  IM    
Affiliation:
Dipartimento di Biochimica G. Moruzzi, via Irnerio 48, Università di Bologna, 40126 Bologna, Italy.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / biosynthesis*
Cell Membrane Permeability / drug effects
Cells, Cultured
DNA, Mitochondrial / genetics*
Digitonin / pharmacology
Female
Humans
Ion Transport
Leigh Disease / genetics,  metabolism*,  pathology*
Male
Mutation / genetics
Pedigree
Protons
Retinitis Pigmentosa / complications*,  genetics,  metabolism,  pathology*
Substrate Specificity
Syndrome
Threonine / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
GP0280Y01//Telethon
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; 0/Protons; 11024-24-1/Digitonin; 56-65-5/Adenosine Triphosphate; 72-19-5/Threonine
Comments/Corrections

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