Mitophagy, the selective removal of damaged mitochondria, is a quality control mechanism which is critical for mitochondrial health. Defects in mitophagy are strongly associated with Parkinson’s Disease (PD), a progressive neurodegenerative movement disorder with high prevalence which is lacking any causal therapeutic treatment option. The development of an effective mitophagy enhancing drug is thus a promising avenue to combat PD.
BNIP3 and NIX are two mitophagy cargo receptors located at the outer mitochondrial membrane that promote mitophagy by recruiting autophagy machinery proteins and orchestrating the formation of an autophagosome around the mitochondrion. Under basal conditions the F box protein FBXL4 efficiently suppresses this pathway via ubiquitination and subsequent degradation of the receptors. Like BNIP3/NIX, FBXL4 is also anchored to the outer mitochondrial membrane where it acts as substrate-recognition subunit of an Skp1-Cullin1-F box (SCF) ubiquitin E3 ligase complex. Importantly, efficient assembly of the functional SCF-FBXL4 complex also depends on the accumulation of the mitochondrial matrix phosphatase PPTC7 at the outer mitochondrial membrane, thus representing the rate-limiting factor for BNIP3/NIX degradation.
This project aims to uncover the molecular mechanism of the FBXL4-mediated ubiquitination of BNIP3/NIX by structural and biochemical characterisation of the complex and its components. The findings will guide the discovery of a novel drug against PD which boosts mitophagy by hampering the assembly of the SCF-FBXL4 complex and the proteasomal degradation of BNIP3/NIX.