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Functional analyses of genes linked to heritable forms of Parkinson’s disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations inPARK15/FBXO7cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and itsDrosophilaorthologue, ntc, share functional homology and explored its role in mitophagyin vivo. We show thatntcmutants partially phenocopyPink1andparkinmutants andntcoverexpression supressesparkinphenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation which triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditionsin vivoand presents a new avenue for therapeutic approaches.

PINK1/parkin are key mediators of stress-induced mitophagy in vitro, but their impact on basal mitophagy in vivo is unclear. Novel Drosophila reporter lines reveal abundant mitophagy in many tissues, including dopaminergic neurons, that is unaffected by loss of PINK1/parkin., The Parkinson’s disease factors PINK1 and parkin are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagy in vivo. We generated transgenic Drosophila melanogaster expressing fluorescent mitophagy reporters to evaluate the impact of Pink1/parkin mutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues, including Parkinson’s disease–relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, in Pink1 or parkin null flies, we did not observe any substantial impact on basal mitophagy. Because these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy in Drosophila. They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure.

Parkinson’s disease factors, PINK1 and parkin, are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagyin vivo. We generated transgenicDrosophilaexpressing fluorescent mitophagy reporters to evaluate the impact ofPink1/parkinmutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues including Parkinson’s disease relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, inPink1orparkinnull flies we did not observe any substantial impact on basal mitophagy. As these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/Parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy inDrosophila. They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure.SummaryPINK1/parkin are key mediators of stress-induced mitophagyin vitrobut their impact on basal mitophagyin vivois unclear. NovelDrosophilareporters lines reveal abundant mitophagy in many tissues including dopaminergic neurons but is unaffected by loss of PINK1/parkin.