# Estrogen receptor beta and mitochondrial permeability transition in Ca2+-induced neuronal injury

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $370,781

## Abstract

Mitochondrial permeability transition (MPT) is an inner membrane permeabilization event, which can result in
irreversible de-energization and swelling of mitochondria, leading to release of pro-death factors.
Mitochondrial Ca2+ overload is the best-characterized trigger of MPT and has been implicated in the
pathogenesis of diverse paradigms of neuronal death, such as ischemia-reperfusion injury, where a large
influx of cytosolic Ca2+ triggers mitochondrial Ca2+ overload. While uncontrolled MPT can result in
mitochondrial disruption, under certain conditions, MPT could provide mitochondria with a Ca2+ release outlet,
allowing Ca2+ recycling and protecting mitochondria from Ca2+ overload. Estrogen receptors (ER) have been
implicated in various paradigms of neuronal injury, and MPT modulation could be one of the mechanisms
whereby they exert their role. Our studies revealed an unprecedented role of the ERβ in modulating MPT. In
mouse brain mitochondria, estrogen decreases mitochondrial Ca2+ capacity in an ERβ and cyclophilin-D
(CyPD, an MPT activator) dependent manner. Mitochondria from ERβ knock out (ERβKO) mice have
reduced sensitivity to cyclosporine A, a potent CyPD inhibitor and CyPD genetic ablation in ERβKO does not
further increase Ca2+ capacity. These results point to ERβ as a novel regulator of Ca2+-dependent MPT that
functionally interacts with CyPD. In this application, we will test the hypothesis that ERβ localized in
mitochondria (mERβ) regulates MPT, independently of transcriptional effects. The goals are to investigate
the mechanisms of MPT modulation by mERβ and to test the effects of MPT modulation by mERβ in models
of neuronal injury that involve mitochondrial Ca2+ toxicity, such as oxygen glucose deprivation (OGD) and
glutamatergic toxicity. To this end we propose 1) to study the mechanisms of regulation of Ca2+-mediated
MPT by ERβ. This regulation will be investigated using a multipronged approach, involving biochemical and
molecular studies. 2) To assess the role of ERβ MPT regulation in neuronal Ca2+-mediated injury. Evidence
suggests that Ca2+ dependent MPT and its regulator CyPD are involved in ischemic neuronal injury. We will
use neuronal OGD and exposure to glutamatergic agents, both well-known paradigms of neuronal toxicity
involving mitochondrial Ca2+ overload, to test the effects of genetic and pharmacological modulation of ERβ.
The impact of the project will be two-fold: first, it will elucidate novel mechanisms of MPT regulation; second,
it will assess if MPT modulation by mERβ could be protective in neuronal injury.

## Key facts

- **NIH application ID:** 9963404
- **Project number:** 5R01NS095692-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Costantino Iadecola
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,781
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963404

## Citation

> US National Institutes of Health, RePORTER application 9963404, Estrogen receptor beta and mitochondrial permeability transition in Ca2+-induced neuronal injury (5R01NS095692-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963404. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*