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

Abstract

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.

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

“…Interestingly, previous studies identified sex-specific differences in mitochondrial function in SOD1 G93A mice that have been suggested to underlie female resilience in this line. Notably, female SOD1 G93A mice have increased activation of the mitochondrial unfolded protein response (UPRmt; Riar et al, 2017), reduced mitochondrial calcium accumulation (Kim et al, 2012) and improved preservation of Complex I function (Cacabelos et al, 2016). However, whether these sex-specific differences in mitochondrial function are mutation-or genetic-background-dependent remains to be determined.…”

Novel behavioural characteristics of the superoxide dismutase 1 G93A (SOD1G93A) mouse model of amyotrophic lateral sclerosis include sex‐dependent phenotypes

“…74 Finally, oestrogen antagonises the P2X7 receptor 75 (overactivation of this receptor is believed to be involved in ALS neurotoxicity 76 ), offering further protection (at least at earlier stages of the disease) in female SOD1 G93A mice. 74 Finally, oestrogen antagonises the P2X7 receptor 75 (overactivation of this receptor is believed to be involved in ALS neurotoxicity 76 ), offering further protection (at least at earlier stages of the disease) in female SOD1 G93A mice.…”

“…Importantly, these processes are also oestrogen receptor-dependent. 74 Finally, oestrogen antagonises the P2X7 receptor 75 (overactivation of this receptor is believed to be involved in ALS neurotoxicity 76 ), offering further protection (at least at earlier stages of the disease) in female SOD1 G93A mice.…”

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

“…In mice subjected to hypoxia-ischemia, mitophagy induction is higher in females than in males and the lower clearance of damaged mitochondria in males may contribute to their greater vulnerability to neuronal death after hypoxia-ischemia [77]. Interestingly, the ERα-dependent UPRmt pathway is higher in females than in males [77, 78]. …”