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Idebenone increases mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration.

ABSTRACT: BACKGROUND: Leber's hereditary optic neuropathy (LHON) is caused by mutations in the complex I subunits of the respiratory chain. Although patients have been treated with idebenone since 1992, the efficacy of the drug is still a matter of debate. METHODS: We evaluated the effect of idebenone in fibroblasts from LHON patients using enzymatic and polarographic measurements. RESULTS: Complex I activity was 42% greater in treated fibroblasts compared to controls (p = 0.002). Despite this complex I activity improvement, the effects on mitochondrial respiration were contradictory, leading to impairment in some cases and stimulation in others. CONCLUSION: These results indicate that idebenone is able to compensate the complex I deficiency in LHON patient cells with variable effects on respiration, indicating that the patients might not be equally likely to benefit from the treatment.

SUBMITTER: Angebault C

PROVIDER: S-EPMC3285568 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Idebenone increases mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration.

Angebault Claire C Gueguen Naïg N Desquiret-Dumas Valérie V Chevrollier Arnaud A Guillet Virginie V Verny Christophe C Cassereau Julien J Ferre Marc M Milea Dan D Amati-Bonneau Patrizia P Bonneau Dominique D Procaccio Vincent V Reynier Pascal P Loiseau Dominique D

BMC research notes 20111222

<h4>Background</h4>Leber's hereditary optic neuropathy (LHON) is caused by mutations in the complex I subunits of the respiratory chain. Although patients have been treated with idebenone since 1992, the efficacy of the drug is still a matter of debate.<h4>Methods</h4>We evaluated the effect of idebenone in fibroblasts from LHON patients using enzymatic and polarographic measurements.<h4>Results</h4>Complex I activity was 42% greater in treated fibroblasts compared to controls (p = 0.002). Despi ...[more]

PMID: 22192149

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Project description:Idebenone is a synthetic quinone that on reduction in cells can bypass mitochondrial Complex I defects by donating electrons to Complex III. The drug is used clinically to treat the Complex I disease Leber's hereditary optic neuropathy (LHON), but has been less successful in clinical trials for other neurodegenerative diseases. NAD(P)H:quinone oxidoreductase 1 (NQO1) appears to be the main intracellular enzyme catalyzing idebenone reduction. However, NQO1 is not universally expressed by cells of the brain. Using primary rat cortical cells pooled from both sexes, we tested the hypotheses that the level of endogenous NQO1 activity limits the ability of neurons, but not astrocytes, to use idebenone as an electron donor to support mitochondrial respiration. We then tested the prediction that NQO1 induction by pharmacological activation of the transcription factor nuclear erythroid 2-related factor 2 (Nrf2) enables idebenone to bypass Complex I in cells with poor NQO1 expression. We found that idebenone stimulated respiration by astrocytes but reduced the respiratory capacity of neurons. Importantly, idebenone supported mitochondrial oxygen consumption in the presence of a Complex I inhibitor in astrocytes but not neurons, and this ability was reversed by inhibiting NQO1. Conversely, recombinant NQO1 delivery to neurons prevented respiratory impairment and conferred Complex I bypass activity. Nrf2 activators failed to increase NQO1 in neurons, but carnosic acid induced NQO1 in COS-7 cells that expressed little endogenous enzyme. Carnosic acid-idebenone combination treatment promoted NQO1-dependent Complex I bypass activity in these cells. Thus, combination drug strategies targeting NQO1 may promote the repurposing of idebenone for additional disorders.SIGNIFICANCE STATEMENT Idebenone is used clinically to treat loss of visual acuity in Leber's hereditary optic neuropathy. Clinical trials for several additional diseases have failed. This study demonstrates a fundamental difference in the way idebenone affects mitochondrial respiration in cortical neurons compared with cortical astrocytes. Cortical neurons are unable to use idebenone as a direct mitochondrial electron donor due to NQO1 deficiency. Our results suggest that idebenone behaves as an NQO1-dependent prodrug, raising the possibility that lack of neuronal NQO1 activity has contributed to the limited efficacy of idebenone in neurodegenerative disease treatment. Combination therapy with drugs able to safely induce NQO1 in neurons, as well as other brain cell types, may be able to unlock the neuroprotective therapeutic potential of idebenone or related quinones.

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Idebenone increases mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration.

Publications

Idebenone increases mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration.

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