Linked Life Data

9914528

Source:http://linkedlifedata.com/resource/pubmed/id/9914528

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
1999-3-5
pubmed:abstractText
Mutations in the tRNA genes of mitochondrial DNA (mtDNA) cause the debilitating MELAS (mitochondrial, myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres) syndromes. These mtDNA mutations affect respiratory chain function, apparently without decreasing cellular ATP concentration [Moudy et al. (1995) PNAS, 92, 729-733]. To address this issue, we investigated the role of mitochondrial ATP synthesis in fibroblasts from MELAS and MERRF patients. The maximum rate of mitochondrial ATP synthesis was decreased by 60-88%, as a consequence of the decrease in the proton electrochemical potential gradient of MELAS and MERRF mitochondria. However, in quiescent fibroblasts neither ATP concentration or the ATP/ADP ratio was affected by the lowered rate of ATP synthesis. We hypothesized that the low ATP demand of quiescent fibroblasts masked the mitochondrial ATP synthesis defect and that this defect might become apparent during higher ATP use. To test this we simulated high energy demand by titrating cells with gramicidin, an ionophore that stimulates ATP hydrolysis by the plasma membrane Na+/K+-ATPase. We found a threshold gramicidin concentration in control cells at which both the ATP/ADP ratio and the plasma membrane potential decreased dramatically, due to ATP demand by the Na+/K+-ATPase outstripping mitochondrial ATP synthesis. In MELAS and MERRF fibroblasts the corresponding threshold concentrations of gramicidin were 2-20-fold lower than those for control cells. This is the first demonstration that cells containing mtDNA mutations are particularly sensitive to increased ATP demand and this has several implications for how mitochondrial dysfunction contributes to disease pathophysiology. In particular, the increased susceptibility to plasma membrane depolarization will render neurons with dysfunctional mitochondria susceptible to excitotoxic cell death.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0014-2956
pubmed:author
pubmed:issnType
Print
pubmed:volume
259
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
462-9
pubmed:dateRevised
2007-7-23
pubmed:meshHeading
pubmed-meshheading:9914528-Adenosine Diphosphate, pubmed-meshheading:9914528-Adenosine Triphosphate, pubmed-meshheading:9914528-Adolescent, pubmed-meshheading:9914528-Adult, pubmed-meshheading:9914528-Cell Death, pubmed-meshheading:9914528-Cell Membrane, pubmed-meshheading:9914528-Child, Preschool, pubmed-meshheading:9914528-Fibroblasts, pubmed-meshheading:9914528-Humans, pubmed-meshheading:9914528-Intracellular Membranes, pubmed-meshheading:9914528-MELAS Syndrome, pubmed-meshheading:9914528-MERRF Syndrome, pubmed-meshheading:9914528-Male, pubmed-meshheading:9914528-Membrane Potentials, pubmed-meshheading:9914528-Middle Aged, pubmed-meshheading:9914528-Mitochondria, pubmed-meshheading:9914528-Models, Biological, pubmed-meshheading:9914528-Mutation, pubmed-meshheading:9914528-Proton-Motive Force, pubmed-meshheading:9914528-RNA, Transfer, pubmed-meshheading:9914528-RNA, Transfer, Leu, pubmed-meshheading:9914528-RNA, Transfer, Lys
pubmed:year
1999
pubmed:articleTitle
Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations.
pubmed:affiliation
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't