A novel role for SENP3 in iron-chelation induced mitophagy for the treatment of Parkinson’s disease

The objective of this thesis was to understand how the iron chelating drug, Deferiprone (DFP), mediates its effects in mitophagy through Parkin/PINK1 independent mechanisms.
DFP is an iron chelating drug currently in clinical trials for the treatment of Parkinson’s disease and has been shown to induce mitophagy independently of the PINK1/Parkin mitophagy pathway. Parkin/PINK1 mutations are the most common causes of autosomal-recessive Parkinson’s disease. However, little is known about the action of DFP in this alternative pathway. Mitophagy is the lysosomal degradation of mitochondria. In sporadic and familial Parkinson’s disease, mitochondrial function can be defective. Mitophagy overcomes this by removing damaged mitochondria, however this can also be impaired, particularly in patients with mutations in Parkin/PINK1.
Evidence from the work carried out in this thesis suggests that SENP3 is important for DFP-induced mitophagy. SENP3 is a deSUMOylation enzyme involved in removing SUMO-2/3 modifications from target proteins. One potential target is Fis1, a mitochondrial membrane protein with links to mitophagy. Through biochemical and microscopy techniques, it was shown that both SENP3 and Fis1 play important roles in DFP-induced mitophagy, with SENP3 acting to deSUMOylate Fis1, a novel SUMO substrate. It is believed that Fis1 in its deSUMOylated state localises better to the mitochondria and is capable of inducing mitophagy.
The work carried out in this thesis highlights an alternative mitophagy pathway through which DFP acts to induce mitophagy. The superfluous nature of Parkin/PINK in this pathway makes it an attractive avenue to explore.