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 ER? in modulating MPT. In mouse brain mitochondria, estrogen decreases mitochondrial Ca2+ capacity in an ER? and cyclophilin-D (CyPD, an MPT activator) dependent manner. Mitochondria from ER? knock out (ER?KO) mice have reduced sensitivity to cyclosporine A, a potent CyPD inhibitor and CyPD genetic ablation in ER?KO does not further increase Ca2+ capacity. These results point to ER? as a novel regulator of Ca2+-dependent MPT that functionally interacts with CyPD. In this application, we will test the hypothesis that ER? localized in mitochondria (mER?) regulates MPT, independently of transcriptional effects. The goals are to investigate the mechanisms of MPT modulation by mER? and to test the effects of MPT modulation by mER? 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 ER?. This regulation will be investigated using a multipronged approach, involving biochemical and molecular studies. 2) To assess the role of ER? 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 ER?. 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 mER? could be protective in neuronal injury.

Public Health Relevance

Neurons depend on mitochondria because they provide energy and are crucial for the maintenance of intracellular calcium. In ischemia, mitochondria do not receive sufficient oxygen and nutrients, and neurons fill up with calcium, leading to mitochondria permeabilization and neuronal death. We will investigate how estrogen receptor and estrogen modulate mitochondrial permeabilization in ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS095692-03
Application #
9501806
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Koenig, James I
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Burstein, Suzanne R; Kim, Hyun Jeong; Fels, Jasmine A et al. (2018) Estrogen receptor beta modulates permeability transition in brain mitochondria. Biochim Biophys Acta Bioenerg 1859:423-433
Kahl, Anja; Anderson, Corey J; Qian, Liping et al. (2018) Neuronal expression of the mitochondrial protein prohibitin confers profound neuroprotection in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab 38:1010-1020
Gorelick, Philip B; Furie, Karen L; Iadecola, Costantino et al. (2017) Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association. Stroke 48:e284-e303