Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy

Abstract

Leber's hereditary optic neuropathy, the most frequent mitochondrial disease due to mitochondrial DNA point mutations in complex I, is characterized by the selective degeneration of retinal ganglion cells, leading to optic atrophy and loss of central vision prevalently in young males. The current study investigated the reasons for the higher prevalence of Leber's hereditary optic neuropathy in males, exploring the potential compensatory effects of oestrogens on mutant cell metabolism. Control and Leber's hereditary optic neuropathy osteosarcoma-derived cybrids (11778/ND4, 3460/ND1 and 14484/ND6) were grown in glucose or glucose-free, galactose-supplemented medium. After having shown the nuclear and mitochondrial localization of oestrogen receptors in cybrids, experiments were carried out by adding 100 nM of 17β-oestradiol. In a set of experiments, cells were pre-incubated with the oestrogen receptor antagonist ICI 182780. Leber's hereditary optic neuropathy cybrids in galactose medium presented overproduction of reactive oxygen species, which led to decrease in mitochondrial membrane potential, increased apoptotic rate, loss of cell viability and hyper-fragmented mitochondrial morphology compared with control cybrids. Treatment with 17β-oestradiol significantly rescued these pathological features and led to the activation of the antioxidant enzyme superoxide dismutase 2. In addition, 17β-oestradiol induced a general activation of mitochondrial biogenesis and a small although significant improvement in energetic competence. All these effects were oestrogen receptor mediated. Finally, we showed that the oestrogen receptor β localizes to the mitochondrial network of human retinal ganglion cells. Our results strongly support a metabolic basis for the unexplained male prevalence in Leber's hereditary optic neuropathy and hold promises for a therapeutic use for oestrogen-like molecules.

Perioperative visual loss after spine surgery

“…Thus far, these explanations are simply theories that require further investigation. Why the male sex appears to be a risk factor for ischemic optic neuropathy during prone position is still a puzzle, but it has been suggested that estrogen may serve a protective role [31] .…”

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…Recently Giordano et al . [71] investigated the effects of oestrogens on cybrids carrying the LHON mutations 11778/ND4, 3460/ND1 and 14484/ND6 in vitro . Treatment with 17β-oestradiol reduced levels of reactive oxygen species (ROS), believed to be responsible for oxidative cell damage which had previously been shown to be raised in LHON cells.…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…For example, the G11778A (ND4) and T14484C (ND6) LHON mutations on subgroups of a mitochondrial haplogroup J or the G3460A (ND1) mutation on the mitochondrial haplotype K background have been associated with increased risk of visual loss [29]. Differences between haplogroups may be partially due to mtDNA quantity, which influences OXPHOS capacity [30] and may account for gender differences in disease penetrance in LHON; there is a suggestion that oestrogens increase mtDNA levels, enhancing oxygen consumption and ATP generation [87]. associated with specific mitochondrial mutations.…”