Positive regulation of human PINK1 and Parkin gene expression by nuclear respiratory factor 1

Abstract

Previous studies have demonstrated that two Parkinson'sdisease-associatedgenes PINK1 and Parkin play a key role in mitochondrial quality control. But until now, the transcriptional regulation of these two genes under normal physiological conditions are not well understood. In this study, the transcriptional regulation of PINK1 and Parkin genes by nuclear respiratory factor 1 (NRF-1) and its effect on PINK1/Parkin-mediated mitophagy were studied. The NRF-1 binding sites in the promoter regions of human PINK1 and Parkin genes were analyzed by JASPER software and were confirmed by chromatin immunoprecipitation (ChIP) assay. The transcriptional activities and the expressions of PINK1 and Parkin genes were positively regulated by NRF-1 in HEK293T cells and in SH-SY5Y cells. Furthermore, NRF-1 over-expression (OE) up-regulated the protein level of full-length PINK1 in CCCP-treated cells, indicating the enhanced PINK1/Parkin-mediated mitophagy. When NRF-1 expression was transient orstableknockdown, the CCCP-induced mitophagy was alleviated as characterized by the reduced protein level of full-length PINK1, the declined ratio of LC3 II to LC3 I, and the decreasedratioof Mt-keimafluorescenceintensityexcited at 552 nm to that excited at 488 nm. In conclusion, NRF-1 has a positive regulatory effect on the transcription of PINK1 and Parkin genes, and involves in mitochondrial quality control through regulating PINK1/Parkin-mediated mitophagy.