c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number2007
JournalAntioxidants
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2023

Keywords

  • amyotrophic lateral sclerosis
  • apoptosis
  • c-Abl
  • endoplasmic reticulum stress
  • mitochondrial fusion
  • mitofusin 2

ASJC Scopus subject areas

  • Food Science
  • Physiology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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