SIM2s directed Parkin-mediated mitophagy promotes mammary epithelial cell differentiation
Lilia SanchezJ ElswoodSteven W. WallCole M. McQueenScott J. PearsonKelly ScribnerElizabeth A. WellbergErin D. GilesMonique RijnkelsWeston W. Porter
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Abstract The functionally differentiated mammary gland adapts to extreme levels of stress from increased demand for energy by activating specific protective mechanisms to support neonatal health. Here, we identify the breast tumor suppressor gene, single-minded 2 s (SIM2s) as a novel regulator of mitophagy, a key component of this stress response. Using tissue-specific mouse models, we found that loss of Sim2 reduced lactation performance, whereas gain (overexpression) of Sim2s enhanced and extended lactation performance and survival of mammary epithelial cells (MECs). Using an in vitro model of MEC differentiation, we observed SIM2s is required for Parkin-mediated mitophagy, which we have previously shown as necessary for functional differentiation. Mechanistically, SIM2s localizes to mitochondria to directly mediate Parkin mitochondrial loading. Together, our data suggest that SIM2s regulates the rapid recycling of mitochondria via mitophagy, enhancing the function and survival of differentiated MECs.Keywords:
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Abstract Background We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsis-induced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. Methods Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. Key results PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin−/− mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkin-dependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. Conclusions These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.
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Much evidence links mitochondrial dysfunction to the death of neurons in Parkinson disease (PD), and is particularly emphasized by our growing understanding of the function of genes linked to recessively inherited PD such as PINK1, parkin and DJ-1. Recent work has revealed an exciting link between the PINK1-Parkin pathway and the autophagic turnover of dysfunctional mitochondrial (mitophagy). We have recently shown that mitofusin is ubiquitinated by Parkin when it is recruited to dysfunctional mitochondria. Recent work also shows that regulated fission and fusion events help segregate dysfunctional mitochondria prior to mitophagy. Here we hypothesize how Parkin-mediated ubiquitination of Mfn may play a role in this mechanism.
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Dysfunctional mitochondria may produce excessive reactive oxygen species, thus inducing DNA damage, which may be oncogenic if not repaired. As a major role of the PINK1-Parkin pathway involves selective autophagic clearance of damaged mitochondria via a process termed mitophagy, Parkin-mediated mitophagy may be a tumor-suppressive mechanism. As an alternative mechanism for tumor inhibition beyond mitophagy, Parkin has been reported to have other oncosuppressive functions such as DNA repair, negative regulation of cell proliferation and stimulation of p53 tumor suppressor function. The authors recently reported that acute ethanol-induced mitophagy in hepatocytes was associated with Parkin mitochondrial translocation and colocalization with accumulated 8-OHdG (a marker of DNA damage and mutagenicity). This finding suggests: (1) the possibility of Parkin-mediated repair of damaged mitochondrial DNA in hepatocytes of ethanol-treated rats (ETRs) as an oncosuppressive mechanism; and (2) potential induction of cytoprotective mitophagy in ETR hepatocytes if mitochondrial damage is too severe to be repaired. Below is a summary of the various roles Parkin plays in tumor suppression, which may or may not be related to mitophagy. A proper understanding of the various tasks performed by Parkin in tumorigenesis may help in cancer therapy by allowing the PINK1-Parkin pathway to be targeted.
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Parkin is a ubiquitin ligase that is involved in the selective removal of dysfunctional mitochondria. This process is termed mitophagy and can assist in mitochondrial quality control. Endurance training can produce adaptations in skeletal muscle toward a more oxidative phenotype, an outcome of enhanced mitochondrial biogenesis. It remains unknown whether Parkin-mediated mitophagy is involved in training-induced increases in mitochondrial content and function. Our purpose was to determine a role for Parkin in maintaining mitochondrial turnover in muscle, and its requirement in mediating mitochondrial biogenesis following endurance exercise training. Wild-type and Parkin knockout (KO) mice were trained for 6 weeks and then treated with colchicine or vehicle to evaluate the role of Parkin in mediating changes in mitochondrial content, function and acute exercise-induced mitophagy flux. Our results indicate that Parkin is required for the basal maintenance of mitochondrial function. The absence of Parkin did not significantly alter mitophagy basally; however, acute exercise produced an elevation in mitophagy flux, a response that was Parkin-dependent. Mitochondrial content was increased following training in both genotypes, but this occurred without an induction of PGC-1α signaling in KO animals. Interestingly, the increased muscle mitochondrial content in response to training did not influence basal mitophagy flux, despite an enhanced expression and localization of Parkin to mitochondria in WT animals. Furthermore, exercise-induced mitophagy flux was attenuated with training in WT animals, suggesting a lower rate of mitochondrial degradation resulting from improved organelle quality with training. In contrast, training led to a higher mitochondrial content, but with persistent dysfunction, in KO animals. Thus, the lack of a rescue of mitochondrial dysfunction with training in the absence of Parkin is the likely reason for the impaired training-induced attenuation of mitophagy flux compared to WT animals. Our study demonstrates that Parkin is required for exercise-induced mitophagy flux. Exercise-induced mitophagy is reduced with training in muscle, likely due to attenuated signaling consequent to increased mitochondrial content and quality. Our data suggest that Parkin is essential for the maintenance of basal mitochondrial function, as well as for the accumulation of normally functioning mitochondria as a result of training adaptations in muscle.
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Mutations in the genes for PINK1 and parkin cause Parkinson’s disease. PINK1 and parkin cooperate in the selective autophagic degradation of damaged mitochondria (mitophagy) in cultured cells. However, evidence for their role in mitophagy in vivo is still scarce. Here, we generated a Drosophila model expressing the mitophagy probe mt-Keima. Using live mt-Keima imaging and correlative light and electron microscopy (CLEM), we show that mitophagy occurs in muscle cells and dopaminergic neurons in vivo, even in the absence of exogenous mitochondrial toxins. Mitophagy increases with aging, and this age-dependent rise is abrogated by PINK1 or parkin deficiency. Knockdown of the Drosophila homologues of the deubiquitinases USP15 and, to a lesser extent, USP30, rescues mitophagy in the parkin-deficient flies. These data demonstrate a crucial role for parkin and PINK1 in age-dependent mitophagy in Drosophila in vivo.
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