PRCC-TFE3 fusion-mediated PRKN/parkin-dependent mitophagy promotes cell survival and proliferation in PRCC-TFE3 translocation renal cell carcinoma

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 (TFE3 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 PRCC-TFE3 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 PRCC-TFE3 tRCC cell line. We found that nuclear-aggregated PRCC-TFE3 fusions constitutively activated expression of the target gene E3 ubiquitin Ligase PRKN, 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 PRCC-TFE3 tRCC.