MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin.
MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin.
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作者：
Yun J;Puri R;Yang H;Lizzio MA;Wu C;Sheng ZH;Guo M
Parkinson's disease (PD) genes PINK1 and parkin act in a common pathway that regulates mitochondrial integrity and quality. Identifying new suppressors of the pathway is important for finding new therapeutic strategies. In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. The suppression is achieved through the ubiquitin-dependent degradation of Mitofusin, which itself causes PINK1/parkin mutant-like toxicity when overexpressed. We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone, leading to lethality in flies and degeneration in mouse cortical neurons. Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD. DOI: http://dx.doi.org/10.7554/eLife.01958.001 Parkinson's disease is the second most common neurodegenerative disorder. Symptoms include tremors, rigidity, and slowness, as well as dementia and depression. While most cases of Parkinson's disease have no known genetic cause, mutations in either of two genes—PINK1 or parkin—are known to lead to the disease. PINK1 and parkin belong to a single pathway that regulates the structure and function of mitochondria, the organelles that generate energy inside cells. Identifying inhibitors of this pathway is critically important for development of future therapies. In addition, previous studies showed that mice with mutations in PINK1 or parkin, as opposed to those in humans and flies, display subtle signs of Parkinson's disease: the fact that these are weak suggests that other unknown proteins or cellular pathways might compensate for loss of the genes. Yun et al. have now identified one such protein by showing that an increase in the level of a Protein called MUL1 counteracts the deleterious effects due to the loss of PINK1 or parkin in fruit flies. MUL1 is a mitochondrial protein that regulates another protein called mitofusin; the role of mitofusin is to promote the fusion of mitochondria. Conversely, removing MUL1 from PINK1 or parkin mutant worsens the symptoms because MUL1 is no longer present to compensate for the defects. Yun et al. also show that MUL1 operates through a pathway that is independent of PINK1/parkin. Moreover, this pathway is found in both flies and mouse neurons, which suggest that it has been conserved during evolution. The work of Yun et al. also suggests that MUL1 as a potential therapeutic target for Parkinson's disease. DOI: http://dx.doi.org/10.7554/eLife.01958.002
