CASK Mediates Oxidative Stress-Induced Microglial Apoptosis-Inducing Factor-Independent Parthanatos Cell Death via Promoting PARP-1 Hyperactivation and Mitochondrial Dysfunction
Journal
Antioxidants (Basel, Switzerland)
Journal Volume
13
Journal Issue
3
Start Page
343
ISSN
2076-3921
Date Issued
2024-03-13
Author(s)
Cheong, Keith Jun Hao
Huang, Duen-Yi
Sekar, Ponarulselvam
Chen, Rou Jhen
Cheng, Irene Han-Juo
Chan, Chi-Ming
Chen, Yuan-Shen
Abstract
Calcium/calmodulin-dependent serine protein kinase (CASK) is a scaffold protein and plays critical roles in neuronal synaptic formation and brain development. Previously, CASK was shown to associate with EGFR to maintain the vulval cell differentiation in . In this study, we explored the role of CASK in CHME3 microglial cells. We found that CASK silencing protects cells from HO-induced cell death by attenuating PARP-1 activation, mitochondrial membrane potential loss, reactive oxygen species production, and mitochondrial fission, but it increases oxidative phosphorylation. The PARP-1 inhibitor olaparib blocks HO-induced cell death, suggesting the death mode of parthanatos. CASK silencing also increases AKT activation but decreases AMPK activation under HO treatment. Pharmacological data further indicate that both signaling changes contribute to cell protection. Different from the canonical parthanatos pathway, we did not observe the AIF translocation from mitochondria into the nucleus, suggesting a non-canonical AIF-independent parthanatos in HO-treated CHME3 cells. Moreover, we found that CASK silencing upregulates the EGFR gene and protein expression and increases HO-induced EGFR phosphorylation in CHME3 microglia. However, EGFR activation does not contribute to cell protection caused by CASK silencing. In conclusion, CASK plays a crucial role in microglial parthanatos upon HO treatment via stimulation of PARP-1 and AMPK but the inhibition of AKT. These findings suggest that CASK might be an ideal therapeutic target for CNS disorders.
Subjects
AKT
AMPK
CASK
EGFR
PARP-1
hydrogen peroxide
microglia
mitochondrial dysfunction
parthanatos
Type
journal article