Document Detail


Human xenomitochondrial cybrids. Cellular models of mitochondrial complex I deficiency.
MedLine Citation:
PMID:  9603924     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The subunits forming the mitochondrial oxidative phosphorylation system are coded by both nuclear and mitochondrial genes. Recently, we attempted to introduce mtDNA from non-human apes into a human cell line lacking mtDNA (rho degrees), and succeeded in producing human-common chimpanzee, human-pigmy chimpanzee, and human-gorilla xenomitochondrial cybrids (HXC). Here, we present a comprehensive characterization of oxidative phosphorylation function in these cells. Mitochondrial complexes II, III, IV, and V had activities indistinguishable from parental human or non-human primate cells. In contrast, a complex I deficiency was observed in all HXC. Kinetic studies of complex I using decylubiquinone or NADH as limiting substrates showed that the Vmax was decreased in HXC by approximately 40%, and the Km for the NADH was significantly increased (3-fold, p < 0.001). Rotenone inhibition studies of intact cell respiration and pyruvate-malate oxidation in permeabilized cells showed that 3 nM rotenone produced a mild effect in control cells (0-10% inhibition) but produced a marked inhibition of HXC respiration (50-75%). Immunoblotting analyses of three subunits of complex I (ND1, 75 and 49 kDa) showed that their relative amounts were not significantly altered in HXC cells. These results establish HXC as cellular models of complex I deficiency in humans and underscore the importance of nuclear and mitochondrial genomes co-evolution in optimizing oxidative phosphorylation function.
Authors:
A Barrientos; L Kenyon; C T Moraes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  273     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1998 Jun 
Date Detail:
Created Date:  1998-07-16     Completed Date:  1998-07-16     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  14210-7     Citation Subset:  IM    
Affiliation:
Department of Neurology, University of Miami, School of Medicine, Miami, Florida 33136, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Respiration / drug effects,  physiology
Cells, Cultured
Clone Cells / metabolism
DNA, Mitochondrial / genetics*
Evolution, Molecular
Hominidae
Humans
Hybrid Cells / metabolism
Kinetics
Mitochondria / metabolism*
NAD / metabolism
NAD(P)H Dehydrogenase (Quinone) / chemistry,  deficiency
Oxidative Phosphorylation*
Oxygen Consumption / physiology
Rotenone / pharmacology
Grant Support
ID/Acronym/Agency:
GM55766/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; 53-84-9/NAD; 83-79-4/Rotenone; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone)

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