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

doi:10.3390/antiox11020314

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	314
Number of pages	20
Journal	Antioxidants (Basel, Switzerland)
Volume	11
Issue number	2
DOIs	https://doi.org/10.3390/antiox11020314
Publication status	Published - 4-Feb-2022

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Musheshe, N., Oun, A., Sabogal-Guáqueta, A. M., Trombetta-Lima, M., Mitchel, S. C., Adzemovic, A., Speek, O., Morra, F., van der Veen, C. H. J. T., Lezoualc'h, F., Cheng, X., Schmidt, M., & Dolga, A. M. (2022). Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity. Antioxidants (Basel, Switzerland), 11(2), [314]. https://doi.org/10.3390/antiox11020314

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title = "Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity",

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.",

author = "Nshunge Musheshe and Asmaa Oun and Sabogal-Gu{\'a}queta, {Ang{\'e}lica Mar{\'i}a} and Marina Trombetta-Lima and Mitchel, {Sarah C} and Ahmed Adzemovic and Oliver Speek and Francesca Morra and {van der Veen}, {Christina H J T} and Frank Lezoualc'h and Xiaodong Cheng and Martina Schmidt and Dolga, {Amalia M}",

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Musheshe, N, Oun, A , Sabogal-Guáqueta, AM , Trombetta-Lima, M , Mitchel, SC, Adzemovic, A, Speek, O, Morra, F, van der Veen, CHJT, Lezoualc'h, F, Cheng, X, Schmidt, M & Dolga, AM 2022, 'Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity', Antioxidants (Basel, Switzerland), vol. 11, no. 2, 314. https://doi.org/10.3390/antiox11020314

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

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SN - 2076-3921

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JO - Antioxidants (Basel, Switzerland)

JF - Antioxidants (Basel, Switzerland)

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