c-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative...

Area of Science:

• Cell Biology
• Neuroscience
• Biochemistry

Background:

• The endoplasmic reticulum (ER) is vital for protein homeostasis.
• ER stress triggers adaptive responses but prolonged stress leads to cell death via oxidative stress and mitochondrial fragmentation.
• Mitochondrial dynamics, including fusion and fission, are crucial for cellular health.

Purpose of the Study:

• To investigate the role of c-Abl tyrosine kinase in ER stress-induced cell death.
• To elucidate the mechanism by which ER stress impacts mitochondrial dynamics.
• To evaluate the therapeutic potential of c-Abl inhibition in a mouse model of amyotrophic lateral sclerosis (ALS).

Main Methods:

• Induction of ER stress in cell cultures.
• Analysis of c-Abl activation and translocation to mitochondria.
• Assessment of MFN2 phosphorylation and mitochondrial morphology.
• Pharmacological and genetic inhibition of c-Abl.
• Administration of c-Abl inhibitor (Nintedanib) in an ALS mouse model.

Main Results:

• ER stress activates c-Abl tyrosine kinase, causing its translocation to mitochondria.
• Activated c-Abl phosphorylates MFN2, a mitochondrial fusion protein, leading to mitochondrial fragmentation.
• Inhibition of c-Abl blocked MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis.
• Nintedanib administration delayed symptom onset in the ALS mouse model.

Conclusions:

• c-Abl acts as a critical mediator linking ER stress to mitochondrial fragmentation and apoptosis through MFN2 phosphorylation.
• Targeting c-Abl represents a potential therapeutic strategy for conditions involving ER stress and mitochondrial dysfunction, such as ALS.