title: Biochemical and molecular basis for mitochondrial cardiomyopathy in neonates and children.
abstract: 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.
authors.affiliation: The Molecular Cardiology Institute, Highland Park, New Jersey 08904, USA. tmci@worldnet.att.net
authors.forename: J
authors.initials: J
authors.lastname: Marin-Garcia
authors.forename: R
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: M J
authors.initials: MJ
authors.lastname: Goldenthal
authors.forename: M E
authors.initials: ME
authors.lastname: Pierpont
mesh_terms: 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
chemical_list: 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