Mitochondria: An Emerging Therapeutic Target for Neurodegeneration

Abstract

Neurodegenerative diseases (NDs) constitute an escalating global health crisis characterised by irreversible neuronal deterioration, resulting in progressive decline of cognitive abilities, motor functions, and ultimately, quality of life. Despite extensive research efforts, current therapeutic approaches remain largely focused on symptom management rather than disease modification. A common feature across various NDs is mitochondrial dysfunction, particularly impaired mitophagy - the selective degradation of damaged mitochondria through autophagy pathways. This quality control mechanism is crucial for maintaining cellular health, especially in post-mitotic neurons where dysfunction can lead to cellular death. Despite the clear link between impaired mitophagy and neurodegeneration, there are currently no clinically approved mitophagy activators, targeting the central nervous system (CNS). This significant therapeutic gap, combined with the rising prevalence of NDs in ageing populations, underscores the urgent need for developing CNS-active mitophagy modulators.

This thesis explores the development of novel small molecule mitophagy activators for treating NDs through three main approaches: optimisation of the p62-mediated mitophagy inducer (PMI) scaffold through hybridisation, structure-activity relationship studies of Urolithin A (UroA), and computational scaffold hopping to identify new chemical entities.