Deficiency of the reduced nicotinamide adenine dinucleotide dehydrogenase component of complex I of mitochondrial electron transport. Fatal infantile lactic acidosis and hypermetabolism with skeletal-cardiac myopathy and encephalopathy.

Hoppel, Charles L.; Kerr, Douglas S.; Dahms, Beverly B.; Roessmann, Uros

doi:10.1172/jci113066

Cited by 157 publications

(86 citation statements)

References 29 publications

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“…The former has been described for a knockout mutation of the 49-kDa(IP) homologue in Neurospora crassa (33). Previously, we interpreted a profile of ETC changes similar to those in this study as a deficit in NADH dehydrogenase (34). However, our present results show that a mutation in another functional unit (IP) in Complex I may affect the activity of NADH dehydrogenase.…”

Section: Table III Electron Transport Assayssupporting

confidence: 82%

Mitochondrial Expression and Function of GAS-1 in Caenorhabditis elegans

Kayser

Morgan

Hoppel

et al. 2001

Journal of Biological Chemistry

156

134

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A mutation in the gene gas-1 alters sensitivity to volatile anesthetics, fecundity, and life span in the nematode Caenorhabditis elegans. gas-1 encodes a close homologue of the 49-kDa iron protein subunit of Complex I of the mitochondrial electron transport chain from bovine heart. gas-1 is widely expressed in the nematode neuromuscular system and in a subcellular pattern consistent with that of a mitochondrial protein. Pharmacological studies indicate that gas-1 functions partially via presynaptic effects. In addition, a mutation in the gas-1 gene profoundly decreases Complex I-dependent metabolism in mitochondria as measured by rates of both oxidative phosphorylation and electron transport. An increase in Complex II-dependent metabolism also is seen in mitochondria from gas-1 animals. There is no apparent alteration in physical structure in mitochondria from gas-1 nematodes compared with those from wild type. These data indicate that gas-1 is the major 49-kDa protein of complex I and that the GAS-1 protein is critical to mitochondrial function in C. elegans. They also reveal the importance of mitochondrial function in determining not only aging and life span, but also anesthetic sensitivity, in this model organism.

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Section: Table III Electron Transport Assayssupporting

confidence: 82%

Mitochondrial Expression and Function of GAS-1 in Caenorhabditis elegans

Kayser

Morgan

Hoppel

et al. 2001

Journal of Biological Chemistry

156

134

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“…A complex IV defect is manifest by deficiency of reducible cytochrome a + a3, low (29), implying that these disorders promote mitochondrial biogenesis. This may compensate partially for the oxidative defect as illustrated by the fact that in our patient COX activity in whole muscle was higher (20% of normal) than that expressed per milligram of mitochondrial protein (10% of normal).…”

Section: Discussionmentioning

confidence: 99%

Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.

Haller¹,

Lewis²,

Estabrook³

et al. 1989

J. Clin. Invest.

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A 27-yr-old woman with lifelong severe exercise intolerance manifested by muscle fatigue, lactic acidosis, and prominent symptoms of dyspnea and tachycardia induced by trivial exercise was found to have a skeletal muscle respiratory chain defect characterized by low levels of reducible cytochromes a + a3 and b in muscle mitochondria and marked deficiency of cytochrome c oxidase (complex IV) as assessed biochemically and immunologically. Investigation of the pathophysiology of the exercise response in the patient revealed low maximal oxygen uptake (1/3 that of normal sedentary women) in cycle exercise and impaired muscle oxygen extraction as indicated by profoundly low maximal systemic arteriovenous oxygen difference (5.8 ml/dl; controls = 15.4±1.4, mean±SD). The increases in cardiac output and ventilation during exercise, normally closely coupled to muscle metabolic rate, were markedly exaggerated (more than two-to threefold normal) relative to oxygen uptake and carbon dioxide production accounting for prominent tachycardia and dyspnea at low workloads. Symptoms in our patient are similar to those reported in other human skeletal muscle respiratory chain defects involving complexes I and III, and the exaggerated circulatory response resembles that seen during experimental inhibition of the mitochondrial respiratory chain. These results suggest that impaired oxidative phosphorylation in working muscle disrupts the normal regulation of cardiac output and ventilation relative to muscle metabolic rate in exercise.

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“…The following enzymes' activities were measured in detergent-solubilized, freshly isolated SSM and IFM using previously described methods (Hoppel et al, 1987;Lesnefsky et al, 1997): NADH-cytochrome c reductase, rotenone-sensitive; NADH-decylubiquinone reductase, rotenone sensitive (complex I); cytochrome oxidase; and citrate synthase were measured in SSM and IFM at 37°C. Outer mitochondrial membrane integrity was assessed by measuring the rate of oxidation of exogenous reduced cytochrome c in the presence and absence of detergent.…”

Section: Methodsmentioning

confidence: 99%

Reversible Blockade of Electron Transport during Ischemia Protects Mitochondria and Decreases Myocardial Injury following Reperfusion

Chen

Moghaddas

Hoppel³

et al. 2006

J Pharmacol Exp Ther

187

206

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Cardiac mitochondria sustain damage during ischemia and reperfusion, contributing to cell death. The reversible blockade of electron transport during ischemia with amobarbital, an inhibitor at the rotenone site of complex I, protects mitochondria against ischemic damage. Amobarbital treatment immediately before ischemia was used to test the hypothesis that damage to mitochondrial respiration occurs mainly during ischemia and that protection of mitochondria during ischemia leads to decreased cardiac injury with reperfusion. Langendorff-perfused Fischer-344 rat hearts were treated with amobarbital (2.5 mM) or vehicle for 1 min immediately before 25 min of global ischemia. Both groups were reperfused for 30 min without additional treatment. Subsarcolemmal (SSM) and interfibrillar (IFM) populations of mitochondria were isolated after reperfusion. Ischemia and reperfusion decreased state 3 and increased state 4 respiration rate in both SSM and IFM. Amobarbital treatment protected oxidative phosphorylation measured following reperfusion and improved the coupling of respiration. Cytochrome c content measured in SSM and IFM following reperfusion decreased in untreated, but not in amobarbitaltreated, hearts. H 2 O 2 release from SSM and IFM isolated from amobarbital-treated hearts during reperfusion was markedly decreased. Amobarbital treatment before ischemia improved recovery of contractile function (percentage of preischemic developed pressure: untreated 51 Ϯ 4%, n ϭ 12; amobarbital 70 Ϯ 4%, n ϭ 11, p Ͻ 0.01) and substantially reduced infarct size (untreated 32 Ϯ 2%, n ϭ 7; amobarbital 13 Ϯ 2%, n ϭ 7, p Ͻ 0.01). Thus, mitochondrial damage occurs mainly during ischemia rather than during reperfusion. Reperfusion in the setting of preserved mitochondrial respiratory function attenuates the mitochondrial release of reactive oxygen species, enhances contractile recovery, and decreases myocardial infarct size.

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Deficiency of the reduced nicotinamide adenine dinucleotide dehydrogenase component of complex I of mitochondrial electron transport. Fatal infantile lactic acidosis and hypermetabolism with skeletal-cardiac myopathy and encephalopathy.

Cited by 157 publications

References 29 publications

Mitochondrial Expression and Function of GAS-1 in Caenorhabditis elegans

Mitochondrial Expression and Function of GAS-1 in Caenorhabditis elegans

Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.

Reversible Blockade of Electron Transport during Ischemia Protects Mitochondria and Decreases Myocardial Injury following Reperfusion

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