Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased activity of complex I (NAD:ubiquinone oxidoreductase) is the most frequent biochemical finding associated with mutation at the base pair 3243 of the mitochondrial DNA. The mutation has been previously shown to lead to a defective translation. We hypothesized that due to an imperfect assembly of complex I subunits the substrate affinity of this enzyme may be lowered and this may be counteracted by increasing the mitochondrial NAD+NADH concentration. Therefore, we studied the effect and mechanism of action of nicotinamide treatment in a MELAS patient with the base pair 3243 mutation. Nicotinamide treatment was initiated after his first stroke-like episode. The blood NAD concentration (representing the intracellular concentration in erythrocytes) increased linearly being 24-fold at 6 weeks of treatment. Blood lactate and pyruvate concentration decreased by 50% within three days and 24 h urine lactate content within 2 weeks and we observed a clinical improvement together with a decrease in the lesion volume in magnetic resonance imaging within the first month. The cellular NAD increase upon nicotinamide administration was probably universal, because it occurred in a time and dose-dependent manner in cultured fibroblasts from both the patient and the controls. Alleviation of the lactate accumulation during the nicotinamide treatment suggests that an increase in the cellular NAD+NADH concentration leads to enhancement of the oxidation of reducing equivalents. However, the Km of complex I for NADH in skeletal muscle from the patient was similar to that of controls. This may indicate that physiologically mitochondrial complex I operates at non-saturating substrate concentration, and this may explain the effect of nicotinamide treatment.
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PMID:Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. 859 19

Decreased activity of mitochondrial complex I and II is implicated in the pathophysiology of progressive supranuclear palsy (PSP) and Huntington's disease (HD), respectively. Both disorders preferentially affect the nucleus striatum, a brain area particularly vulnerable to excitotoxic damage. To gain insights into the pathophysiology of neuronal degeneration during PSP and HD, here we studied the possible interplay between excitatory transmission and mitochondrial complex I and II inhibition in the development of striatal damage. By using in vitro neurophysiological recordings and cell swelling measures in corticostriatal slices, we found that stimulation of NMDA receptors significantly contributed to the neurotoxic effects of 3-nitropropionic acid (3-NP) but not of rotenone, selective inhibitors of mitochondrial complex II and I, respectively. We also found that blockade of a subset of NMDA receptors containing the NR2B subunit was sufficient to protect the striatum from the injurious effects of 3-NP, an effect unrelated to the prevention of membrane excitation by NMDA receptor stimulation. Pharmacological inhibition of dopamine receptors, conversely, failed to modulate both rotenone- and 3-NP-induced neuronal damage. Our results indicate that the cellular mechanisms leading to striatal neuronal death are different following inhibition of distinct mitochondrial complexes of the respiratory chain, implying that neuroprotective strategies in PSP and HD must significantly differ.
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PMID:NR2B-containing NMDA receptors promote the neurotoxic effects of 3-nitropropionic acid but not of rotenone in the striatum. 1691 72