c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration
Martinez, Alexis
Pontificia Universidad Catolica de Chile
Lamaizon, Cristian M.
Pontificia Universidad Catolica de Chile
Valls, Cristian
Pontificia Universidad Catolica de Chile
Llambi, Fabien
St Jude Children's Research Hospital
Leal, Nancy
Pontificia Universidad Catolica de Chile
Fitzgerald, Patrick
St Jude Children's Research Hospital
Guy, Cliff
St Jude Children's Research Hospital
Kaminski, Marcin M.
St Jude Children's Research Hospital
van Zundert, Brigitte
Pontificia Univ Catolica Chile CARE UC
Cancino, Gonzalo I.
Pontificia Universidad Catolica de Chile
Dulcey, Andres E.
National Institutes of Health (NIH) - USA
Zanlungo, Silvana
Pontificia Universidad Catolica de Chile
Marugan, Juan J.
National Institutes of Health (NIH) - USA
Hetz, Claudio
Universidad de Chile
Green, Douglas R.
St Jude Children's Research Hospital
Alvarez, Alejandra R.
Pontificia Universidad Catolica de Chile
Journal
Antioxidants
ISSN
2076-3921
Open Access
gold
Volume
12
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.