Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy

Hum Mol Genet. 2015 Dec 15;24(24):6921-31. doi: 10.1093/hmg/ddv396. Epub 2015 Sep 26.


Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease characterized by degeneration of retinal ganglion cells (RGCs) and consequent optic nerve atrophy. Peculiar features of LHON are incomplete penetrance and gender bias, with a marked male prevalence. Based on the different hormonal metabolism between genders, we proposed that estrogens play a protective role in females and showed that these hormones ameliorate mitochondrial dysfunction in LHON through the estrogen receptors (ERs). We also showed that ERβ localize to the mitochondria of RGCs. Thus, targeting ERβ may become a therapeutic strategy for LHON specifically aimed at avoiding or delaying the onset of disease in mutation carriers. Here, we tested the effects of ERβ targeting on LHON mitochondrial defective metabolism by treating LHON cybrid cells carrying the m.11778G>A mutation with a combination of natural estrogen-like compounds that bind ERβ with high selectivity. We demonstrated that these molecules improve cell viability by reducing apoptosis, inducing mitochondrial biogenesis and strongly reducing the levels of reactive oxygen species in LHON cells. These effects were abolished in cells with ERβ knockdown by silencing receptor expression or by using specific receptor antagonists. Our observations support the hypothesis that estrogen-like molecules may be useful in LHON prophylactic therapy. This is particularly important for lifelong disease prevention in unaffected LHON mutation carriers. Current strategies attempting to combat degeneration of RGCs during the acute phase of LHON have not been very effective. Implementing a different and preemptive approach with a low risk profile may be very helpful.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Respiration
  • Cell Survival / drug effects
  • Cells, Cultured
  • Estrogen Receptor beta / antagonists & inhibitors*
  • Estrogen Receptor beta / genetics
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mutation
  • Optic Atrophy, Hereditary, Leber / metabolism
  • Optic Atrophy, Hereditary, Leber / prevention & control*
  • Organelle Biogenesis
  • Oxidative Stress / drug effects
  • Oxygen Consumption
  • Phytoestrogens / therapeutic use*
  • Retinal Ganglion Cells / metabolism


  • Estrogen Receptor beta
  • Phytoestrogens