Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity
Nshunge Musheshe,
Asmaa Oun,
Angélica María Sabogal-Guáqueta,
Marina Trombetta-Lima,
Sarah C. Mitchel,
Ahmed Adzemovic,
Oliver Speek,
Francesca Morra,
Christina H. J. T. van der Veen,
Frank Lezoualc’h,
Xiaodong Cheng,
Martina Schmidt,
Amalia M. Dolga
Affiliations
Nshunge Musheshe
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Asmaa Oun
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Angélica María Sabogal-Guáqueta
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Marina Trombetta-Lima
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Sarah C. Mitchel
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Ahmed Adzemovic
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Oliver Speek
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Francesca Morra
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Christina H. J. T. van der Veen
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Frank Lezoualc’h
Inserm UMR-1297, Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse Paul Sabatier, 31400 Toulouse, France
Xiaodong Cheng
Department of Integrative Biology & Pharmacology, Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX 7000, USA
Martina Schmidt
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Amalia M. Dolga
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
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.
