Human Molecular Genetics, Vol 8, 1967-1974, Copyright © 1999 by Oxford University Press
J Houtek, P Klement, D Floryk, H Antonicka, J Hermanska, M Kalous, H Hansikova, H Hout'kova, SK Chowdhury, t Rosipal, S Kmoch, L Stratilova and J Zeman
We report a new type of fatal mitochondrial disorder caused by selective
deficiency of mitochondrial ATP synthase (ATPase). A hypotrophic newborn
from a consanguineous marriage presented severe lactic acidosis,
cardiomegaly and hepatomegaly and died from heart failure after 2 days. The
activity of oligomycin-sensitive ATPase was only 31-34% of the control,
both in muscle and heart, but the activities of cytochrome c oxidase,
citrate synthase and pyruvate dehydrogenase were normal. Electrophoretic
and western blot analysis revealed selective reduction of ATPase complex
but normal levels of the respiratory chain complexes I, III and IV. The
same selective deficiency of ATPase was found in cultured skin fibroblasts
which showed similar decreases in ATPase content, ATPase hydrolytic
activity and level of substrate-dependent ATP synthesis (20-25, 18 and
29-33% of the control, respectively). Pulse-chase labelling of patient
fibroblasts revealed low incorporation of [(35)S]methionine into assembled
ATPase complexes, but increased incorporation into immunoprecipitated
ATPase subunit beta, which had a very short half- life. In contrast, no
difference was found in the size and subunit composition of the assembled
and newly produced ATPase complex. Transmitochondrial cybrids prepared from
enucleated fibroblasts of the patient and rho degrees cells derived from
143B. TK(-)human osteosarcoma cells fully restored the ATPase activity, ATP
synthesis and ATPase content, when compared with control cybrids. Likewise,
the pattern of [(35)S]methionine labelling of ATPase was found to be normal
in patient cybrids. We conclude that the generalized deficiency of
mitochondrial ATPase described is of nuclear origin and is caused by
altered biosynthesis of the enzyme.
ARTICLES
A novel deficiency of mitochondrial ATPase of nuclear origin
Department of Bioenergetics, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, CZ 142 20 Prague 4, Czech Republic,
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