TFE3 (transcription factor binding to IGHM enhancer 3) nuclear translocation and transcriptional activity has been implicated in PINK1-PRKN/parkin-dependent mitophagy. However, the transcriptional control governing the mitophagy in TFE3/Xp11.2 translocation renal cell carcinoma ( tRCC) is largely unknown. Here, we investigated the role and mechanisms of PRCC-TFE3 fusion protein, one of TFE3 fusion types in TFE3 tRCC, in governing mitophagy to promote development of tRCC. We observed and analyzed mitophagy, transcriptional control of PRCC-TFE3 on PINK1-PRKN-dependent mitophagy, PRCC-TFE3 fusions nuclear translocation, cancer cell survival and proliferation under mitochondrial oxidative damage in tRCC cell line. We found that nuclear-aggregated PRCC-TFE3 fusions constitutively activated expression of the target gene E3 ubiquitin ligase , leading to rapid PINK1-PRKN-dependent mitophagy that promoted cell survival under mitochondrial oxidative damage as well as cell proliferation through decreasing mitochondrial ROS formation. However, nuclear translocation of TFE3 fusions escaped from PINK1-PRKN-dependent mitophagy. Furthermore, we confirmed that PRCC-TFE3 fusion accelerated mitochondrial turnover by activating PPARGC1A/PGC1α-NRF1. In conclusion, our findings indicated a major role of PRCC-TFE3 fusion-mediated mitophagy and mitochondrial biogenesis in promoting proliferation of tRCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496718 | PMC |
http://dx.doi.org/10.1080/15548627.2020.1831815 | DOI Listing |
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