TY - JOUR
T1 - Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity
AU - Musheshe, Nshunge
AU - Oun, Asmaa
AU - Sabogal-Guáqueta, Angélica María
AU - Trombetta-Lima, Marina
AU - Mitchel, Sarah C
AU - Adzemovic, Ahmed
AU - Speek, Oliver
AU - Morra, Francesca
AU - van der Veen, Christina H J T
AU - Lezoualc'h, Frank
AU - Cheng, Xiaodong
AU - Schmidt, Martina
AU - Dolga, Amalia M
PY - 2022/2/4
Y1 - 2022/2/4
N2 - 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.
AB - 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.
U2 - 10.3390/antiox11020314
DO - 10.3390/antiox11020314
M3 - Article
C2 - 35204198
SN - 2076-3921
VL - 11
JO - Antioxidants (Basel, Switzerland)
JF - Antioxidants (Basel, Switzerland)
IS - 2
M1 - 314
ER -