c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration
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 oxi...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/11/2007 |
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| author | Alexis Martinez Cristian M. Lamaizon Cristian Valls Fabien Llambi Nancy Leal Patrick Fitzgerald Cliff Guy Marcin M. Kamiński Nibaldo C. Inestrosa Brigitte van Zundert Gonzalo I. Cancino Andrés E. Dulcey Silvana Zanlungo Juan J. Marugan Claudio Hetz Douglas R. Green Alejandra R. Alvarez |
| author_facet | Alexis Martinez Cristian M. Lamaizon Cristian Valls Fabien Llambi Nancy Leal Patrick Fitzgerald Cliff Guy Marcin M. Kamiński Nibaldo C. Inestrosa Brigitte van Zundert Gonzalo I. Cancino Andrés E. Dulcey Silvana Zanlungo Juan J. Marugan Claudio Hetz Douglas R. Green Alejandra R. Alvarez |
| author_sort | Alexis Martinez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T17:04:22Z |
| format | Article |
| id | doaj.art-52442aebd7684326868078bfe18e45e8 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T17:04:22Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-52442aebd7684326868078bfe18e45e82023-11-24T14:26:03ZengMDPI AGAntioxidants2076-39212023-11-011211200710.3390/antiox12112007c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and NeurodegenerationAlexis Martinez0Cristian M. Lamaizon1Cristian Valls2Fabien Llambi3Nancy Leal4Patrick Fitzgerald5Cliff Guy6Marcin M. Kamiński7Nibaldo C. Inestrosa8Brigitte van Zundert9Gonzalo I. Cancino10Andrés E. Dulcey11Silvana Zanlungo12Juan J. Marugan13Claudio Hetz14Douglas R. Green15Alejandra R. Alvarez16Cell Signaling Laboratory, Department of Cell and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileCell Signaling Laboratory, Department of Cell and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileCell Signaling Laboratory, Department of Cell and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USACell Signaling Laboratory, Department of Cell and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USABasal Center for Aging and Regeneration, Pontificia Universidad Católica de Chile (CARE UC), Santiago 8331150, ChileBasal Center for Aging and Regeneration, Pontificia Universidad Católica de Chile (CARE UC), Santiago 8331150, ChileLaboratory of Neurobiology, Department of Cell and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileEarly Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD 20850, USADepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O’Higgins 340, Santiago 8331150, ChileEarly Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD 20850, USABiomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago 8330015, ChileDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USACell Signaling Laboratory, Department of Cell and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileThe 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.https://www.mdpi.com/2076-3921/12/11/2007c-Ablmitofusin 2apoptosismitochondrial fusionamyotrophic lateral sclerosisendoplasmic reticulum stress |
| spellingShingle | Alexis Martinez Cristian M. Lamaizon Cristian Valls Fabien Llambi Nancy Leal Patrick Fitzgerald Cliff Guy Marcin M. Kamiński Nibaldo C. Inestrosa Brigitte van Zundert Gonzalo I. Cancino Andrés E. Dulcey Silvana Zanlungo Juan J. Marugan Claudio Hetz Douglas R. Green Alejandra R. Alvarez c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration Antioxidants c-Abl mitofusin 2 apoptosis mitochondrial fusion amyotrophic lateral sclerosis endoplasmic reticulum stress |
| title | c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration |
| title_full | c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration |
| title_fullStr | c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration |
| title_full_unstemmed | c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration |
| title_short | c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration |
| title_sort | c abl phosphorylates mfn2 to regulate mitochondrial morphology in cells under endoplasmic reticulum and oxidative stress impacting cell survival and neurodegeneration |
| topic | c-Abl mitofusin 2 apoptosis mitochondrial fusion amyotrophic lateral sclerosis endoplasmic reticulum stress |
| url | https://www.mdpi.com/2076-3921/12/11/2007 |
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