title: Antioxidants partially restore glutamate transport defect in leber hereditary optic neuropathy cybrids.
abstract: 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.
authors.affiliation: Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy. gessica.sala@unimib.it
authors.forename: Gessica
authors.initials: G
authors.lastname: Sala
authors.forename: Federica
authors.initials: F
authors.lastname: Trombin
authors.forename: Simone
authors.initials: S
authors.lastname: Beretta
authors.forename: Lucio
authors.initials: L
authors.lastname: Tremolizzo
authors.forename: Paola
authors.initials: P
authors.lastname: Presutto
authors.forename: Monica
authors.initials: M
authors.lastname: Montopoli
authors.forename: Marianna
authors.initials: M
authors.lastname: Fantin
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006822:Hybrid Cells; D029242:Optic Atrophy, Hereditary, Leber / Q000378:metabolism*; D050050:Protein Carbonylation
chemical_list: D000975:Antioxidants; D018698:Glutamic Acid