Investigating Novel Mitophagy Modulators in Cell Models of Parkinson’s Disease

Abstract

Mitochondrial dysfunction serves as a central driver of Parkinson’s Disease (PD). Our
findings demonstrated that AZD5438, a multi-kinase inhibitor (MKI), mitigates
mitochondrial damage and apoptosis in PD cell models and elucidates the kinase
signalling regulated by AZD5438 using a sophisticated and highly sensitive PamChip®
array covering a broad kinome, including PhosphoTyrosine Kinase (PTK) and
Serine/Threonine Kinase (STK). AZD5438 demonstrated significant anti-apoptotic
effects in SH-SY5Y neuroblastoma and H4 neuroglioma cell lines. It is highly glycolytic
with protection enhanced by glucose-driven ATP production. High-resolution imaging
and transmission electron microscopy (TEM) demonstrated the preservation of
mitochondrial network complexity and cristae architecture. Mechanistically, AZD5438
suppressed CCCP stress-induced mitochondrial fission by decreasing Drp1
phosphorylation at Ser616 and reducing its recruitment to the outer mitochondrial
membrane, without altering OPA-1-mediated fusion. AZD548 confers better protection
than CHIR99021, a specific GSK3 inhibitor, maintains SIRT1 levels at basal levels,
and downregulates mTOR activity in oxidative stress. In addition, AZD5438 preserves
the mitochondrial network better than rapamycin (a positive regulator of mitophagy)
following acute mitochondrial stress. Kinome profiling showed that AZD5438 exhibits
context-dependent activity under metabolic stress. AZD5438 strongly suppresses
oxidative stress-responsive and inflammatory pathways by synergistically inhibiting
GSK3a/b, CDKs, ERK, stress-activated MAPKs (JNK and p38), and CILK1. In a
Rotenone mouse model, AZD5438 showed preservation of dopaminergic neurons and
maintenance of neuronal morphology in the substantia nigra pars compacta (SNpc).
The results showed AZD5438 regulated Drp-1-dependent dynamics and reduced
stress kinase signalling, which together preserved the mitochondrial network and
dopaminergic neurons. Together, these findings support the potential repurposing of
AZD5438 for neuro-mitochondrial protection in PD and related neurodegenerative
disorders.

Date of Award	9 Dec 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	James B Uney (Supervisor) & Oscar Cordero Llana (Supervisor)