Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity.

Nshunge Musheshe,Ahmed Adzemovic,Angélica María Sabogal-Guáqueta,Sarah C Mitchel,Francesca Morra,Frank Lezoualc’H,Xiaodong Cheng,Martina Schmidt,Asmaa Oun,Marina Trombetta-Lima,Oliver Speek,Amalia M Dolga,Christina H J T Van Der Veen

doi:10.3390/antiox11020314

Abstract

Exchange proteins directly activated by cAMP (Epac) proteins are implicated in a wide range of cellular functions including oxidative stress and cell survival. Mitochondrial-dependent oxidative stress has been associated with progressive neuronal death underlying the pathology of many neurodegenerative diseases. The role of Epac modulation in neuronal cells in relation to cell survival and death, as well as its potential effect on mitochondrial function, is not well established. In immortalized hippocampal (HT-22) neuronal cells, we examined mitochondria function in the presence of various Epac pharmacological modulators in response to oxidative stress due to ferroptosis. Our study revealed that selective pharmacological modulation of Epac1 or Epac2 isoforms, exerted differential effects in erastin-induced ferroptosis conditions in HT-22 cells. Epac1 inhibition prevented cell death and loss of mitochondrial integrity induced by ferroptosis, while Epac2 inhibition had limited effects. Our data suggest Epac1 as a plausible therapeutic target for preventing ferroptosis cell death associated with neurodegenerative diseases.

Highlights

Introduction published maps and institutional affilThe hallmarks of ferroptosis include accumulation of intracellular iron and oxidative stress, via excessive production of reactive oxygen species (ROS), lipid peroxidation, loss of mitochondria morphology, and cell death
We have shown that pharmacological inhibition and/or silencing of Epac1 is protective against erastin-induced ferroptosis, and presents Cyclic adenosine monophosphate (cAMP)-Epac1 as a plausible therapeutic target to prevent ferroptosis-associated cell death and in turn, might alleviate symptoms that contribute to the progression of neurodegeneration
To investigate the role of Exchange proteins directly activated by cAMP (Epac) signaling in ferroptosis, first we investigated their cellular localization

Summary

Introduction

The hallmarks of ferroptosis include accumulation of intracellular iron and oxidative stress, via excessive production of reactive oxygen species (ROS), lipid peroxidation, loss of mitochondria morphology, and cell death. These processes encompass characteristics observed in neurodegenerative diseases, including Alzheimer’s disease (AD) [1,2,3,4,5]. Conditional deletion of glutathione peroxidase 4 (GPX4), a major mitochondrial ROS-metabolizing enzyme, in the cerebral cortex and hippocampus, caused severe deficits in spatial memory and mediated neurodegeneration in the hippocampi of mice, capturing the pathophysiology of AD [6].

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