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Antioxidants partially restore glutamate transport defect in leber hereditary optic neuropathy cybrids
Author(s) -
Sala Gessica,
Trombin Federica,
Beretta Simone,
Tremolizzo Lucio,
Presutto Paola,
Montopoli Monica,
Fantin Marianna,
Martinuzzi Andrea,
Carelli Valerio,
Ferrarese Carlo
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21773
Subject(s) - leber's hereditary optic neuropathy , rotenone , glutamate receptor , optic neuropathy , point mutation , respiratory chain , oxidative stress , biology , mitochondrion , mutation , chemistry , genetics , biochemistry , anatomy , optic nerve , gene , receptor
Leber hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss resulting from retinal ganglion cell degeneration. Despite the important role of respiratory chain deficiency and oxidative stress induced by mtDNA point mutations affecting complex I, excitotoxic injury has been postulated as a concurrent pathogenic factor. We used transmitochondrial cybrid cell lines constructed using enucleated fibroblasts from three LHON probands carrying the most severe 3460/ND1 mutation and three controls as mitochondria donors, and the osteosarcoma‐derived mtDNA‐less cells, to study the possible efficacy of two selected antioxidant compounds in preventing glutamate uptake reduction previously observed in LHON cybrids. We demonstrated that two antioxidants, Trolox and decylubiquinone, partially restore glutamate transport impairment occurring in LHON cybrids. Rotenone, a classic complex I inhibitor, did not worsen the glutamate uptake defect present in LHON cybrids under basal conditions but significantly reduced glutamate transport in control cybrids. Furthermore, we observed that LHON cybrids showed an increased protein carbonylation under basal conditions, not further affected by rotenone and partially counteracted by antioxidants. Our findings strengthen the hypothesis that the complex I defect associated with LHON causes free radical overproduction, which is responsible for glutamate transport inhibition. We suggest that selected antioxidants may be clinically tested in LHON patients and relatives to restore glutamate uptake defect caused by LHON‐associated free radical overproduction. © 2008 Wiley‐Liss, Inc.