Abstract
Loss of function of parkin leads to mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One dogma is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, the first dogma is not applicable; for the second dogma, our study suggests that Parkin mediates mitochondrial dysfunction through the synergy of both Marf and mitochondrial protein mRpL18 got from our genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, we found that impaired Parkin upregulated both transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing mRpL18 accumulation outside mitochondria. Consequently, cytosolic-accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways together drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, our study unveils a new facet of how Parkin regulates mitochondrial morphology, which provides new insights for the understanding and treatment of Parkinson's disease.
