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.article.number2007
dc.contributor.authorMartinez Saavedra, Alexis
dc.contributor.authorLamaizon Muñoz, Cristián Nicolás
dc.contributor.authorValls Jimenez, Cristián
dc.contributor.authorLlambi, Fabien
dc.contributor.authorLeal Reyes, Nancy Valeria
dc.contributor.authorFitzgerald, Patrick
dc.contributor.authorGuy, Cliff
dc.contributor.authorKaminsk,i Marcin M.
dc.contributor.authorInestrosa Cantin, Nibaldo
dc.contributor.authorvan Zundert, Brigitte
dc.contributor.authorCancino, Gonzalo
dc.contributor.authorDulcey, Andrés E.
dc.contributor.authorZanlungo Matsuhiro, Silvana
dc.contributor.authorMarugan, Juan J.
dc.contributor.authorHetz, Claudio
dc.contributor.authorGreen, Douglas R.
dc.contributor.authorAlvarez Rojas, Alejandra
dc.date.accessioned2024-04-15T08:00:39Z
dc.date.available2024-04-15T08:00:39Z
dc.date.issued2023
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.
dc.description.abstractThe endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, andsorting 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
dc.description.funderAgencia Nacional de Investigación y Desarrollo
dc.description.funderFondo Nacional de Ciencia y Tecnología
dc.description.funderFONDAP
dc.fechaingreso.objetodigital2024-08-30
dc.format.extent3 páginas
dc.fuente.origenScopus
dc.identifier.doi10.3390/antiox12112007
dc.identifier.eisbn9783110775907
dc.identifier.eissn1579-3699
dc.identifier.isbn9783110775877
dc.identifier.issn20763921
dc.identifier.pubmedid38001860
dc.identifier.scopusidSCOPUS_ID:85178361388
dc.identifier.scopusidWOS:001108186200001
dc.identifier.scopusidSCOPUS_ID:85178361388
dc.identifier.urihttps://doi.org/10.3390/antiox12112007
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/85111
dc.identifier.wosidWOS:001108186200001
dc.information.autorucFacultad de Ciencias Biológicas; Alvarez Rojas, Alejandra ; 0000-0002-8129-9280; 83681
dc.information.autorucFacultad de Ciencias Biológicas; Martinez Saavedra, Alexis; S/I; 131991
dc.information.autorucEscuela de Química; Lamaizon Muñoz, Cristián Nicolás; 0000-0001-8515-3804; 1027517
dc.information.autorucFacultad de Ciencias Biológicas; Valls Jimenez, Cristián ; 0009-0000-0517-1069; 179040
dc.information.autorucFacultad de Ciencias Biológicas; Leal Reyes, Nancy Valeria; S/I; 10604
dc.information.autorucFacultad de Ciencias Biológicas; Inestrosa Cantin, Nibaldo; 0000-0003-3118-9726; 26312
dc.information.autorucFacultad de Ciencias Biológicas; Zanlungo Matsuhiro, Silvana; 0000-0001-8383-9829; 72650
dc.issue.numero11
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final561
dc.pagina.inicio542
dc.publisherDe Gruyter
dc.relation.ispartofHandbook of Latin American Environmental Aesthetics
dc.revistaAntioxidants
dc.rightsacceso abierto
dc.subjectAmyotrophic lateral sclerosis
dc.subjectApoptosis
dc.subjectc-Abl
dc.subjectEndoplasmic reticulum stress
dc.subjectMitochondrial fusion
dc.subjectMitofusin 2
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlec-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration
dc.typeartículo
dc.volumen12
sipa.codpersvinculados83681
sipa.codpersvinculados131991
sipa.codpersvinculados1027517
sipa.codpersvinculados179040
sipa.codpersvinculados10604
sipa.codpersvinculados26312
sipa.codpersvinculados72650
sipa.indexScopus
sipa.trazabilidadCarga WOS-SCOPUS;15-04-2024
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