Sex specific activation of the ERα axis of the mitochondrial UPR (UPRmt) in the G93A-SOD1 mouse model of familial ALS

Hum Mol Genet. 2017 Apr 1;26(7):1318-1327. doi: 10.1093/hmg/ddx049.


The mitochondrial unfolded protein response (UPRmt) is a transcriptional program aimed at restoring proteostasis in mitochondria. Upregulation of mitochondrial matrix proteases and heat shock proteins was initially described. Soon thereafter, a distinct UPRmt induced by misfolded proteins in the mitochondrial intermembrane space (IMS) and mediated by the estrogen receptor alpha (ERα), was found to upregulate the proteasome and the IMS protease OMI. However, the IMS-UPRmt was never studied in a neurodegenerative disease in vivo. Thus, we investigated the IMS-UPRmt in the G93A-SOD1 mouse model of familial ALS, since mutant SOD1 is known to accumulate in the IMS of neural tissue and cause mitochondrial dysfunction. As the ERα is most active in females, we postulated that a differential involvement of the IMS-UPRmt could be linked to the longer lifespan of females in the G93A-SOD1 mouse. We found a significant sex difference in the IMS-UPRmt, because the spinal cords of female, but not male, G93A-SOD1 mice showed elevation of OMI and proteasome activity. Then, using a mouse in which G93A-SOD1 was selectively targeted to the IMS, we demonstrated that the IMS-UPRmt could be specifically initiated by mutant SOD1 localized in the IMS. Furthermore, we showed that, in the absence of ERα, G93A-SOD1 failed to activate OMI and the proteasome, confirming the ERα dependence of the response. Taken together, these results demonstrate the IMS-UPRmt activation in SOD1 familial ALS, and suggest that sex differences in the disease phenotype could be linked to differential activation of the ERα axis of the IMS-UPRmt.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Dependent Proteases / genetics
  • ATP-Dependent Proteases / metabolism
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Disease Models, Animal
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Heat-Shock Proteins / genetics
  • High-Temperature Requirement A Serine Peptidase 2
  • Humans
  • Male
  • Mice
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Sex Characteristics
  • Superoxide Dismutase / genetics*
  • Unfolded Protein Response / genetics


  • Estrogen Receptor alpha
  • Heat-Shock Proteins
  • Mitochondrial Proteins
  • SOD1 G93A protein
  • Superoxide Dismutase
  • ATP-Dependent Proteases
  • Serine Endopeptidases
  • mitochondrial intermembrane space protease
  • HTRA2 protein, human
  • High-Temperature Requirement A Serine Peptidase 2
  • Htra2 protein, mouse
  • Proteasome Endopeptidase Complex

Supplementary concepts

  • Amyotrophic lateral sclerosis 1