Investigating the mitophagy-independent activities of PINK1 central to mitochondrial function and Parkinson's disease.

Maintaining a network of functional mitochondria is essential for cellular survival. PINK1, a mitochondrial serine-threonine kinase, is central to sensing mitochondrial health and initiating selective degradation of compromised mitochondria. Whilst the mechanism by which PINK1 initiates mitophagy at the outer-membrane of dysfunctional mitochondria has been well characterised, evidence suggests PINK1 is additionally imported into the mitochondrial matrix. However, its activities here remain poorly-understood. PINK1 mutations are a leading cause of early-onset Parkinson’s disease (PD) thus understanding the entirety of PINK1 functions and how disease-associated mutations impact these, is central to unravelling Parkinson's aetiology. This project will investigate the activities and interactions of PINK1 in the mitochondrial matrix. The impact of PD mutations on PINK1 import and matrix function will be assessed alongside analysis of how mutant PINK1 activity compromises mitochondrial activity and therefore health more broadly. Neuronal models will be used to assess how mitochondrial dysfunction associated with PD-linked mutations affecting PINK1 activity leads to degeneration of dopaminergic neurones, the hallmark of Parkinson’s disease. Should a more comprehensive understanding of PINK1 function in mitochondria be obtained, late-stage investigations will aim to assess whether PINK1 (or its interacting partners) can be therapeutically targeted to restore robust mitochondrial function in neurones.