Biochemical and molecular basis for mitochondrial cardiomyopathy in neonates and children.
Defects in myocardial bioenergetics have been reported in patients with cardiomyopathy but their molecular basis and role in pathophysiology remain unclear. We sought to establish a molecular basis for cardiac mitochondrial respiratory enzyme abnormalities frequently present (75%) in a group of 16 children (including 2 neonates) with end-stage cardiomyopathy. Decreased specific activity levels were found in complexes I, III, IV and V but not in II, the only complex that is entirely nuclear encoded. Sequence analysis of cardiac mtDNA revealed 4 patients harbouring heteroplasmic mtDNA mutations in cytb, tRNAArg, and ND5 at highly conserved positions. These mutations were present neither in controls nor in patients without enzymatic defect. In addition, 4 patients exhibited marked reduction in cardiac mtDNA levels. The basis for respiratory enzyme abnormalities can be explained in a subset of our patients as a result of either pathogenic mtDNA mutation or depletion. Patients harbouring both DNA and enzymatic defects fulfil rigorous criteria defining mitochondrial cardiomyopathy.
Marin-Garcia
J
J
The Molecular Cardiology Institute, Highland Park, New Jersey 08904, USA. tmci@worldnet.att.net
Ananthakrishnan
R
R
Goldenthal
M J
MJ
Pierpont
M E
ME
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000293:Adolescent; D009202:Cardiomyopathies / Q000235:genetics*; D002352:Carrier Proteins; D002675:Child, Preschool; D003573:Cytochrome b Group / Q000235:genetics; D004272:DNA, Mitochondrial / Q000737:chemistry; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000201:enzymology; D017240:Mitochondrial Myopathies / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D012347:RNA, Transfer, Arg / Q000235:genetics; D017422:Sequence Analysis, DNA
D002352:Carrier Proteins; D003573:Cytochrome b Group; D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D012347:RNA, Transfer, Arg; D009247:NADH, NADPH Oxidoreductases; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; C020439:oligomycin sensitivity-conferring protein