Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increase in mitochondrial biogenesis in mammalian cells requires a coordinated increase in the expression of a number of nuclear genes that encode mitochondrial proteins. To examine the regulatory mechanisms involved, we used specific anti-sense RNA probes to estimate the cellular concentrations of mRNA transcripts of two such nuclear genes in rabbit tibialis anterior muscles subjected in vivo to 10-21 days of indirect electrical stimulation. The unstimulated contralateral muscle in the same animals provided a base line for comparison. Change in expression of mitochondrial proteins was assessed in terms of the enzymatic capacity of citrate synthase and cytochrome oxidase, which increased 2.1-fold after 10 days and 5.5- and 4.1-fold, respectively, after 21 days of stimulation. As a proportion of total cellular RNA, messenger RNA encoding subunit beta of F1-ATPase increased 2.2-fold over control levels after 10 days and 2.3-fold after 21 days; mRNA encoding subunit VIC of cytochrome oxidase increased 1.3-fold and 1.9-fold over control levels after stimulation for 10 and 21 days, respectively. These changes were not attributable to nonspecific effects of stimulation on all mRNA transcripts, since aldolase A mRNA decreased to 26% of control levels after 21 days of stimulation. Furthermore, mRNA transcripts from these nuclear genes encoding mitochondrial proteins did not increase to the same extent as mRNA transcripts of mitochondrial genes such as cytochrome b, which increased 5.9-fold after 21 days of stimulation. We conclude that the increase in mitochondrial biogenesis induced by electrical stimulation of skeletal muscle is supported by pretranslational regulation of expression of nuclear genes encoding mitochondrial proteins. There are, however, indications that translational or post-translational regulatory events may also be involved.
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PMID:Adaptation of skeletal muscle to increased contractile activity. Expression nuclear genes encoding mitochondrial proteins. 288 Aug 44

In the rat kidney, NaK-ATPase activity increased between days 19 and 20 of gestation (+50%) and between 1 and 24 h after birth (+20%), requiring an increased energy supply. In order to determine whether mitochondrial changes were involved, renal mitochondrial development was investigated from day 19 of gestation to 1 day after birth. Slot-blot analyses of mitochondrial-DNA/nuclear-DNA ratio and determination of citrate synthase activity showed a doubling in the mitochondrial pool between days 19 and 20 of gestation. In isolated mitochondria, oxygen consumption remained unchanged between days 19 and 20 of gestation, and then it was enhanced between days 20 and 21 of gestation (+70%) and between 1 and 24 h after birth (+50%). We also focused on one of the respiratory-chain complexes, ATP synthase, and measured its activity and content during the perinatal period. We demonstrated increases in both activity and content of ATP synthase between days 20 and 21 of gestation and between 1 and 24 h after birth, thus suggesting that changes in ATP synthase activity are ascribed to an increase in the mitochondrial density of ATP synthase complexes. Moreover, the mitochondrial ATP/ADP ratio only increased between 1 and 24 h (+90%), indicating a critical step in the renal respiratory-chain maturation at that time. We therefore conclude that the postnatal enhancement of renal mitochondrial oxidative capacity might depend on protein synthesis de novo and on changes in the adenine nucleotide concentrations.
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PMID:Perinatal maturation of rat kidney mitochondria. 783 86

Recent studies have suggested that modifications in mitochondrial F1-adenosinetriphosphatase (ATPase) activity may play an important role in the regulation of myocardial oxidative phosphorylation. The goal of the present study was to develop and characterize an assay of F1-ATPase activity that could be performed repeatedly on an intact heart under various physiological states. With the use of submitochondrial particles prepared from biopsy samples of canine myocardium, we found reproducible F1-ATPase activity when normalized to the activity of the intramitochondrial enzyme citrate synthase. The oligomycin-sensitive component of the ATPase activity was found to be mainly F1-ATPase. F1-ATPase activity of normal myocardium increased by incubation in high salt-pH buffer, suggesting baseline inhibition. Five minutes after global ischemia, F1-ATPase activity decreased to 60% of baseline. Hypoxia for 10 min resulted in no significant change in F1-ATPase activity. With phenylephrine infusion, myocardial oxygen consumption more than doubled, whereas F1-ATPase activity increased by approximately 30%. Both returned to baseline levels after discontinuation of the drug. With the use of an assay developed to measure F1-ATPase activity of intact myocardium, changes of the enzyme activity were found during both ischemia and at increased work loads. These data suggest that alterations of F1-ATPase activity may contribute to the regulation of myocardial oxidative phosphorylation.
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PMID:Mitochondrial F1-ATPase activity of canine myocardium: effects of hypoxia and stimulation. 802 1

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.
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PMID:Heart mitochondria response to alcohol is different than brain and liver. 874 11

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.
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PMID:Mitochondrial dysfunction after fetal alcohol exposure. 889 23

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.
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PMID:A novel deficiency of mitochondrial ATPase of nuclear origin. 1048 64

Previous studies in our laboratory demonstrated significant changes in bovine heart mitochondrial bioenergetics during fetal growth and development. To further understand mitochondrial biogenesis in early human development, the activity and subunit content levels of specific mitochondrial enzymes in fetal and neonatal heart were determined. Comparing early gestation (EG, 45-65 day) later gestation (LG, 85-110 day) and neonate (birth-1 month), specific activity of citrate synthase (CS), a Krebs cycle enzyme showed a 2 fold increase from EG to LG and a 2 fold increase from LG to neonate. Specific activities of complex IV and complex V increased similarly 1.8-2 fold from EG to LG. However during the later fetal period from LG to neonate, complex IV activity increased only 1.3 fold and complex V showed no significant increase. Peptide content of COX-II subunit increased 2 fold from EG to LG and by 3.5 fold from LG to neonate. Levels of COX-IV and ATP synthase alpha subunits were undetectable in EG hearts, clearly detectable in LG heart and 3 fold increased from LG to neonate. Unexpectedly, mitochondrial transcription factor A (mt-TFA) levels were not significantly different during these developmental stages. Mitochondrial DNA (mtDNA) levels increased 1.8 fold from EG to LG, and 3.8 fold increase from EG to neonate and correlated with CS activity levels. In conclusion, these data indicate coordinated regulation of some nuclear-encoded (COX-IV and CS activity) and mitochondrial components (COX-II and mtDNA), and strongly suggest that mitochondrial content increases particularly during the early fetal cardiac development and reveal a distinct pattern of regulation for mt-TFA.
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PMID:Heart mitochondrial DNA and enzyme changes during early human development. 1097 57

Previous studies have shown that undernutrition induces an impairment of the respiratory muscle function in patients with chronic lung disease. To explain this, we hypothesized that undernutrition could decrease oxidative metabolism in the diaphragm. We therefore examined the effect of prolonged undernutrition on diaphragm mitochondrial oxygen uptake with pyruvate and palmitate as substrates in adult rats. Ten rats served as controls (CTL). Ten nutritionally deprived rats (ND) received 40% of their estimated daily nutrition. Five weeks of undernutrition induced a 33% decrease in state 3 respiration with pyruvate plus malate as substrate (993 +/- 171 versus 1488 +/- 167 nmol atomic O/mg/min, P < 0.01) and a 39% decrease with palmitate plus malate (516 +/- 89 versus 850 +/- 165 nmol atomic O/mg/min, P < 0.05). With succinate plus rotenone, there was no significant difference in the respiratory rate between groups. In the ND group, we found a significant decrease in citrate synthase activity (P < 0.01), and also in reduced nicotinamine adenine dinucleotide (NADH) dehydrogenase activity (P < 0.05), which cannot alone induce such a state 3 respiratory decrease. This showed that undernutrition in rat diaphragm does not induce an alteration in protein complexes I, II, III, and IV, or the F complex containing the mitochondrial ATPase of the electron transport chain. In conclusion, the main result of this study was that prolonged undernutrition induced a decrease in mitochondrial respiration secondary to a significant reduction in NADH generation by the Krebs cycle, which may affect respiratory muscle function with implications for patient care.
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PMID:Effect of prolonged undernutrition on rat diaphragm mitochondrial respiration. 1180 76

A mechanism decreasing oxidative metabolism during normal cell division and growth is expected to direct substrates toward biosyntheses rather than toward complete oxidation to CO(2). Hence, any event decreasing oxidative phosphorylations (OXPHOS) could provide a proliferating advantage to a transformed or tumor cell in an oxidative tissue. To test this hypothesis, we studied mitochondrial enzymes, DNA and OXPHOS protein content in three types of renal tumors from 25 patients. Renal cell carcinomas (RCCs) of clear cell type (CCRCCs) originate from the proximal tubule and are most aggressive. Chromophilic RCCs, from similar proximal origin, are less aggressive. The benign renal oncocytomas originate from collecting duct cells. Mitochondrial enzyme and DNA contents in all tumor types or grades differed significantly from normal tissue. Mitochondrial impairment increased from the less aggressive to the most aggressive RCCs, and correlated with a considerably decreased content of OXPHOS complexes (complexes II, III, and IV of the respiratory chain, and ATPase/ATP synthase) rather than to the mitochondrial content (citrate synthase and mitochondrial (mt)DNA). In benign oncocytoma, some mitochondrial parameters (mtDNA, citrate synthase, and complex IV) were increased 4- to 7-fold, and some were slightly increased by a factor of 2 (complex V) or close to normal (complexes II and III). A low content of complex V protein was found in all CCRCC and chromophilic tumors studied. However F(1)-ATPase activity was not consistently decreased and its impairment was associated with increased aggressiveness in CCRCCs. Immunodetection of free F(1)-sector of complex V demonstrated a disturbed assembly/stability of complex V in several CCRCC and chromophilic tumors. All results are in agreement with the hypothesis that a decreased OXPHOS capacity favors faster growth or increased invasiveness.
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PMID:Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma. 1201 48

The mechanisms of nitric oxide (NO) signaling include binding to the iron centers in soluble guanylate cyclase and cytochrome c oxidase and posttranslational modification of proteins by S-nitrosation. Low levels of NO control mitochondrial number in cells, but little is known of the impact of chronic exposure to high levels of NO on mitochondrial function in endothelial cells. The focus of this study is the interaction of NO with mitochondrial respiratory complexes in cell culture and the effect this has on iron homeostasis. We demonstrate that chronic exposure of endothelial cells to NO decreased activity and protein levels of complexes I, II, and IV, whereas citrate synthase and ATP synthase were unaffected. Inhibition of these respiratory complexes was accompanied by an increase in cellular S-nitrosothiol levels, modification of cysteines residues, and an increase in the labile iron pool. The NO-dependent increase in the free iron pool and inhibition of complex II was prevented by inhibition of mitochondrial protein synthesis, consistent with a major contribution of the organelle to iron homeostasis. In addition, inhibition of mitochondrial protein synthesis was associated with an increase in heat shock protein 60 levels, which may be an additional mechanism leading to preservation of complex II activity.
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PMID:Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: role of mitochondrial respiratory complexes and heat shock proteins. 1469 Dec 59


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