c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration
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Fecha
2023-11
Profesor/a Guía
Facultad/escuela
Idioma
en
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Título del volumen
Editor
Multidisciplinary Digital Publishing Institute (MDPI)
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Licencia CC
Attribution 4.0 International Deed (CC BY 4.0)
Licencia CC
https://creativecommons.org/licenses/by/4.0/
Resumen
The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation. © 2023 by the authors.
Notas
Indexación: Scopus
Palabras clave
Amyotrophic Lateral Sclerosis, Apoptosis, c-Abl, Endoplasmic Reticulum Stress, Mitochondrial Fusion, Mitofusin 2
Citación
Antioxidants. Volume 12, Issue 11. November 2023. Article number 2007
DOI
10.3390/antiox12112007