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.