In vivo assessment of immune-metabolic effects of mitophagy modulators for neuroinflammation

Overview

This research program investigates how modulating mitophagy—the cellular quality-control process that removes damaged mitochondria—can influence neuroinflammation and neurometabolic dysfunction, with a focus on multiple sclerosis (MS). Mitochondrial dysregulation and neuroinflammation are increasingly recognized as interdependent drivers of neurodegeneration, making mitophagy a compelling therapeutic target. The platform integrates laboratory-based screening of candidate compounds with advanced human neuroimaging to assess therapeutic potential in patients.

The approach addresses a critical translational gap: while pharmacological mitophagy modulation has shown promise in animal and cell models, effects can be disease-dependent, with evidence suggesting that excessive mitophagy may worsen MS pathology. By combining controlled in vitro assays with in vivo human imaging, the program aims to identify which existing licensed compounds that cross the blood-brain barrier could deliver therapeutic benefit for neuroinflammatory conditions.

Technical specifications

In vitro capabilities:

• Mitophagy visualization and quantification in live and fixed cells using the Mitophagy Detection Kit (Dojindo) via confocal microscopy and flow cytometry
• SDS-PAGE analysis of mitophagy-related protein expression changes
• Mitochondrial function assessment using the Seahorse Analyser (Agilent), measuring cellular oxygen consumption
• Cell viability and mitochondrial membrane potential evaluation using fluorescent reporters
• Screening of existing licensed compounds known to modulate mitophagy and penetrate the blood-brain barrier

In vivo imaging techniques:

• Diffusion-Weighted MRI for assessment of glial morphometry and white matter integrity
• Diffusion-Weighted MRS for microstructural analysis in specific brain regions
• 1H-MRS for neurometabolic profiling, including lactate measurement
• qBOLD (quantitative Blood Oxygen Level Dependent imaging) for cerebral oxygen metabolism assessment

Technology readiness level

The in vitro screening methodology is established and operational, with validated protocols for mitophagy detection, protein analysis, and mitochondrial function assessment. The team has an extensive publication track record applying multimodal quantitative imaging to neuroinflammation and neurometabolism studies in humans, including work on systemic inflammatory challenges and MS patient populations. Clinical translation is supported through the Brighton and Sussex Medical School and regional NHS partnerships. The program is positioned to advance candidate compounds from in vitro validation through to human pilot trials in MS patients, with the imaging infrastructure ready to measure treatment effects on tissue integrity, neuroinflammation, and neurometabolism.