Mitochondrial function in children with idiopathic dilated cardiomyopathy.
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Adolescent↗
Biomedical subjects
M J Goldenthal
Publications and source records attributed to M J Goldenthal.
A point mutation in the cytb gene of cardiac mtDNA associated with complex III deficiency in ischemic cardiomyopathy.
We report a high incidence of reduced respiratory Complex III activity in heart muscle concomitant with the presence of a specific mutation in cytochrome b (cytb) in patients with ischemic cardiomyopathy. This C-->A mutation at nt 15452 converts the 236th residue of cytb from a leucine to isoleucine, is heteroplasmic and was observed in only 2 of 43 controls. Complex III activity is reduced (> 50%) in 5 of 6 patients with the C-->A15452 mutation suggesting that the cytb mutation is responsible for decreased Complex III activity and may play a role in the pathophysiology of ischemic cardiomyopathy.
Adult↗
Specific mitochondrial DNA deletions in canine myocardial ischemia.
The effect of myocardial ischemia on mitochondrial DNA (mtDNA) structure and the presence of specific mtDNA deletions was determined using the model of Ameroid constriction of canine coronary arteries. The incidence of specific deletions was high in both the endocardial and epicardial tissues perfused by the occluded vessel as compared to myocardial tissues perfused by the unconstricted vessels. Our results show that specific mtDNA deletions similar to the 5 kb and 7.4 kb human mtDNA deletions occur following canine myocardial ischemia. However the presence of these deletions did not correlate with specific mitochondrial enzyme defects.
Animals↗
Mitochondrial dysfunction after fetal alcohol exposure.
Specific mitochondrial enzyme activities and mRNA levels were measured in the heart, brain, and liver tissues of a group of 1-day-old neonatal rats whose mothers were alcohol-fed during pregnancy and compared with a control group. The results show a significant decrease in mitochondrial ATP synthase activity in both the brain and liver, as well as a decrease in complex III activity in the liver of rats exposed to alcohol. Other mitochondrial enzymes activities (e.g., citrate synthase, cytochrome c oxidase, and complex I), as well as specific mitochondrial transcript levels, were not significantly affected. Heart mitochondrial enzyme activities were not significantly affected. These data reveal that a tissue-specific response occurs after fetal exposure to alcohol and may explain some of the cellular events occurring in fetal alcohol syndrome resulting in abnormal growth and neurological development.
ATP Synthetase Complexes↗
Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy.
OBJECTIVE: Structural changes in human mitochondrial DNA (mtDNA) have been implicated in a number of clinical conditions with dysfunctions in oxidative phosphorylation called OX-PHOS diseases, some of which have cardiac involvement. The objective of this study was to assess the frequency and extent of specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy. METHODS: DNA extracted from tissue derived from the left ventricle of 41 patients with idiopathic dilated cardiomyopathy and 17 controls was amplified by polymerase chain reaction using specific primers to assess the incidence and proportion of 5-kb and 7.4-kb deletions in mitochondrial DNA. RESULTS: In reactions using primers to detect the 5-kb deletion, an amplified product of 593 bp was found in low abundance relative to undeleted mitochondrial DNA but with high frequency in a number of controls and patients. A second deletion of 7.4 kb in size was also frequently present in controls and patients. In contrast to previous reports, these deletions were found to be present in both controls and in cardiomyopathic patients, 18 years and younger, including several infants. The 7.4-kb deletion was prominently increased in both frequency and in its proportion relative to undeleted mitochondrial DNA in patients 40 years and older with idiopathic dilated cardiomyopathy. CONCLUSIONS: At variance with current literature our study reports a significant presence of both 5 and 7.4-kb deletions in the young and a higher frequency and quantity of the 7.4-kb deletion in the older cardiomyopathic patients in comparison with controls. The increased accumulation of the 7.4-kb deletion as both a function of aging and cardiomyopathy is suggestive that this specific mitochondrial DNA deletion arises more likely as an effect of heart dysfunction rather than as a primary cause of cardiomyopathy.
Adolescent↗
Mitochondrial dysfunction in spontaneous inbred turkey cardiomyopathy.
Mitochondrial enzyme activities were examined in cardiac tissues of turkeys with spontaneous inbred cardiomyopathy. Marked declines in specific enzyme activities were noted for respiratory complexes III and V ranging from 65-90% of the control values. No significant differences in complexes I, IV and citrate synthase nor in mitochondrial DNA copy number were detected. These results suggest that specific mitochondrial enzyme defects occur in cardiac tissues during spontaneous inbred turkey cardiomyopathy.
Animals↗
Novel mutations in mitochondrial cytochrome b in fatal post partum cardiomyopathy.
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Adult↗
Heart mitochondria response to alcohol is different than brain and liver.
Specific mitochondrial enzyme activities, mitochondrial DNA copy number, and mRNA levels were measured in heart, brain, and liver tissues of a group of alcohol-fed rats and compared with a control group. The results show a significant increase in mitochondrial enzyme activities (citrate synthase, complex IV, complex III, complex I, and complex V), as well as an increase in mitochondrial DNA in the cardiac tissue of the alcohol-fed animals. These data are indicative of an increase in mitochondrial number in the cardiac tissue that may occur as the result of an adaptive response to the alcoholic insult. However, in the liver and brain of the alcohol-treated rat, specific mitochondrial activities were decreased, in particular, complex III and ATP synthase, whereas levels of other mitochondrial enzymes (e.g., citrate synthase, specific mitochondrial transcripts, and mitochondrial DNA levels) do not seem to be affected. These data suggest that a tissue-specific response to alcohol exists that may have a common molecular mechanism in brain and liver, but is different in the heart.
Age Factors↗
Localized mitochondrial dysfunction in canine myocardial ischemia.
Effects of myocardial ischemia on mitochondrial enzymes and mitochondrial DNA (mtDNA) were examined using the model of Ameroid constriction of canine cardiac vessels. Endocardium supplied by constricted coronary arteries was found to have significantly lower citrate synthase and complex IV activities compared to values obtained from either epicardium supplied by constricted vessels or endocardium supplied by unconstricted coronary arteries. Neither significant differences in mtDNA copy number nor changes in respiratory complexes I, III and V were detected. These results suggest that highly localized, specific mitochondrial enzyme changes result from chronic myocardial ischemia.
Animals↗
Mitochondrial gene expression during bovine cardiac growth and development.
The expression of both mitochondrial and nuclear genes encoding enzymes involved in electron transport and oxidative phosphorylation was examined in bovine cardiac tissue during early growth, development and aging. The steady state level of mRNAs for mitochondrial genes including ATPase 6. COXII and cyt b increased 2.5-4-fold relative to early fetal levels in late fetal and young adult tissues and showed a marked decline (30-50%) in older adult tissues. Similar results were found with the nuclear genes, COXVB and ATP-beta synthase showing coordinate regulation of the two genomes. An increase in mtDNA copy number correlated with the increase in transcript level. Enzyme activity levels for NADH dehydrogenase and cytochrome c oxidase showed a similar trend, albeit of lesser magnitude. These activity levels contrasted with the activity level of an entirely nuclear-encoded mitochondrial enzyme, citrate synthase, which increased not only throughout development but in the older adult tissue. This study indicates that there is a pattern of increasing mitochondrial and nuclear gene expression for OXPHOS enzymes in developing cardiac tissue and decreasing OXPHOS gene expression in the aging heart.
Animals↗
Mitochondrial dysfunction in a case of fatal infantile cardiomyopathy.
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Cardiomyopathy, Hypertrophic↗
Cardiomyopathy and abnormal mitochondrial function.
The diagnosis of cardiomyopathy is mainly based on clinical and morphological criteria. While metabolic, viral, chemical, genetic, and immunological factors are often proposed as causes of cardiomyopathy, little is known about the role of the respiratory chain and other biochemical mitochondrial defects in this group of diseases. Research on the biochemistry and molecular biology of cardiomyopathies offers an opportunity for a better understanding of the pathogenesis and for finding specific therapy.
Adult↗
Presence of a mitochondrial DNA deletion in fetal and adult bovine cardiac tissue.
A deletion of about 5.3 kilobases has been detected in the mitochondrial DNA of bovine cardiac tissue. This deletion appears to be somatic in origin given its sporadic presence in the various heart compartments examined. Cardiac tissue derived from developmental stages including fetal, early and older adult animals harbored this mutation with increased levels (100-1000 fold) found in older adults. The deleted region of the mitochondrial genome maps to relatively the same area (deleting ATPase6, COXIII, ND2, ND4 and a portion of ND5) as the common 5 kb deletion reported in humans, but its presence in fetal tissue, as well as its decreased age dependence distinguish it relative to the reported human deletion.
Aging↗
Isolation and characterization of maltose non utilizing (mnu) mutants mapping outside the MAL1 locus in Saccharomyces cerevisiae.
The MAL1 locus of Saccharomyces cerevisiae comprises three genes necessary for maltose utilization. They include regulatory, maltose transport and maltase genes designated MAL1R, MAL1T and MAL1S respectively. Using a MAL1 strain transformed with an episomal, multicopy plasmid carrying the MAL2 locus, five recessive and one dominant mutant unable to grow on maltose, but still retaining a functional MAL1 locus were isolated. All the mutants could use glycerol, ethanol, raffinose and sucrose as a sole carbon source; expression of the maltase and maltose permease genes was severely and coordinately reduced. Only the dominant mutant failed to accumulate the MAL1R mRNA.
Blotting, Northern↗
Mitochondrial DNA of the blowfly Phormia regina: restriction analysis and gene localization.
A study of an invertebrate mitochondrial genome, that of the blowfly Phormia regina, has been initiated to compare its structural and functional relatedness to other metazoan mitochondrial genomes. A restriction map of mitochondrial DNA (mtDNA) isolated from sucrose gradient-purified mitochondria has been established using a combination of single and double restriction endonuclease digestions and hybridizations with isolated mtDNA fragments, revealing a genome size of 17.5 kilobases (kb). A number of mitochondrial genes including those encoding the 12 S and 16 S ribosomal RNA, the cytochrome c oxidase I subunit (COI) and an unidentified open reading frame (URF2) have been located on the Phormia mtDNA by Southern blot analysis using as probes both isolated mtDNA fragments and oligonucleotides derived from the sequences of previously characterized genes from rat and Drosophila yakuba mtDNAs. These data indicate that for those regions examined, the mitochondrial genome organization of blowfly mtDNA is the same as that of Drosophila yakuba, the order being COI-URF2-12 S-16 S. These data also report the presence of an A + T-rich region, located as a 2.5-kb region between the URF2 and the 12 S rRNA genes, and its amplification by the polymerase chain reaction is described.
Animals↗
Induction of the lutropin/choriogonadotropin receptor in rat ovary during luteinization.
Molecular analysis of the induction of the lutropin/choriogonadotropin receptor during the process of luteinization of the rat ovary was performed. The appearance of receptor binding activity and an immunological analysis of the receptor using Triton solubilized membrane proteins show little receptor present in luteal tissue through day 3 subsequent to hCG treatment, with some in day 4, and a marked increase by day 5. A similar pattern was found in the analysis of RNA hybridizing to several probes derived from the published cDNA sequence suggesting that receptor induction occurs primarily at the level of transcription.
Animals↗
Genetic mapping and biochemical analysis of mutants in the maltose regulatory gene of the MAL1 locus of Saccharomyces cerevisiae.
The MAL1 locus of Saccharomyces cerevisiae comprises three genes necessary for maltose utilization: a regulatory (MALR), a maltose transport (MALT) and a maltase gene (MALS). A fine structure genetic map of the MAL1R gene was constructed and the order of mutations was confirmed by plasmid-mediated chromosomal recombination. The mutations cluster non-randomly within the 5' half of the gene, where the putative DNA binding domain of the encoded protein is located. Only mutations mal1R-22 and MAL1R-72 map in the 3' terminal half of the gene; these mutations cause a different pattern of transcriptional regulation of plasmid-borne MAL6T genes. Experiments supporting a direct involvement of the MALR-encoded protein in carbon catabolite repression of MAL gene expression are reported.
Blotting, Northern↗
Regulation of MAL gene expression in yeast: gene dosage effects.
Both the MAL1 and MAL6 loci in Saccharomyces strains have been shown by functional and structural studies to comprise a cluster of at least three genes necessary for maltose utilization. They include regulatory, maltose transport and maltase genes designated MALR, MALT and MALS, respectively. Subclones of each gene derived from the MAL6 locus were inserted into the multicopy shuttle plasmid YEp13, introduced into MAL1 and mal1 strains and the effects of altered gene dosage of each gene, or a combination of them, on MAL gene expression investigated. MAL1 strains transformed with a plasmid carrying the MAL6S gene showed coordinate four to five fold increases in both maltase enzyme activity and its mRNA, whereas no increase in maltose transport activity or of MALT mRNA was observed when MAL6T was present on multicopy plasmids. The presence of the MAL6R gene on a multicopy plasmid led to greatly increased transcription of both inducible and constitutive mRNAs with homology to the regulatory gene; it also gave rise to two fold increases in both induced maltase mRNA levels and enzyme activity, but only in the presence of maltose. However, it had no apparent effect on the accumulation of MALT mRNA. Finally, the induction kinetics of plasmid-borne and chromosomal MALS and MALT gene expression were examined under conditions of altered gene dosage of the MAL6 regulatory and structural genes. The results of these experiments indicate that MALR encodes a trans-acting positive activator that requires maltose for induction of MALS and MALT transcription even when the regulatory gene is present on a multicopy plasmid. Maltose transport can be a rate-limiting factor in MAL gene expression, at least in the early stages of induction. The regulation of the MALS and MALT genes, whose activities are coordinately induced in MAL1 strains by maltose, may in fact exhibit some important differences.
Escherichia coli↗