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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dc.contributor.authorMartinez, Alexis
dc.contributor.authorLamaizon, Cristian M.
dc.contributor.authorValls, Cristian
dc.contributor.authorLlambi, Fabien
dc.contributor.authorLeal, Nancy
dc.contributor.authorFitzgerald, Patrick
dc.contributor.authorGuy, Cliff
dc.contributor.authorKamiński, Marcin M.
dc.contributor.authorInestrosa, Nibaldo C.
dc.contributor.authorvan Zundert, Brigitte
dc.contributor.authorCancino, Gonzalo I.
dc.contributor.authorDulcey, Andrés E.
dc.contributor.authorZanlungo, Silvana
dc.contributor.authorMarugan, Juan J.
dc.contributor.authorHetz, Claudio
dc.contributor.authorGreen, Douglas R.
dc.contributor.authorAlvarez, Alejandra R.
dc.date.accessioned2025-01-27T18:21:18Z
dc.date.available2025-01-27T18:21:18Z
dc.date.issued2023-11
dc.descriptionIndexación: Scopus
dc.description.abstractThe 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.
dc.description.urihttps://www.mdpi.com/2076-3921/12/11/2007
dc.identifier.citationAntioxidants. Volume 12, Issue 11. November 2023. Article number 2007
dc.identifier.doi10.3390/antiox12112007
dc.identifier.issn2076-3921
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/63301
dc.language.isoen
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.rights.licenseAttribution 4.0 International Deed (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectApoptosis
dc.subjectc-Abl
dc.subjectEndoplasmic Reticulum Stress
dc.subjectMitochondrial Fusion
dc.subjectMitofusin 2
dc.titlec-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration
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