| Popis: |
Background Mitophagy is a major determinant for pulmonary artery smooth muscle cell (PASMC) proliferation in pulmonary hypertension (PH). Accumulating evidence shows that long non-coding RNAs (lncRNAs) encoded by nucleus are powerful regulators of mitophagy process in various diseases. However, the role of mitochondrial genome-encoded noncoding RNA, LncND5, in PH is poorly studied. Methods We performed quantitative real-time PCR, RNA fluorescence in situ hybridization and immunofluorescence analysis to determine LncND5 expression in human PASMCs. The corresponding biological functions were mainly assessed using western blot, immunofluorescence, JC-1 staining and transmission electron microscopy in human PASMCs. RNA pull-down, RNA immunoprecipitation, flow cytometry and immunofluorescence identified the mechanism of LncND5 regulate mitophagy. Results we found that mitochondrial lncRNA is, LncND5, repressed by exposing hypoxia. Mechanistically, LncND5 activate complex Ⅰ by combining with MT-ND5 at the 1086-1159bp of LncND5 in mitochondria to regulate release of mitochondria ROS, leading to mitophagy. In addition, LncND5 represses mitophagy by directly interacting with HMGCS1 in cytoplasm. Then we demonstrated that LncND5 was translocated from mitochondria to cytoplasm via TDP-43. Conclusions The study uncovers the regulatory mechanism of a new lncRNA encoded by mitochondrial genome, LncND5, in PASMC mitophagy by binding to MT-ND5 at the 1086-1159bp of LncND5 in mitochondria. In addition, LncND5 regulates mitophagy by directly interacting with HMGCS1 in cytoplasm. TDP-43 as a transporter mediate LncND5 translocating from mitochondria to cytoplasm. Altogether, our findings suggest that targeting LncND5 may be a potential therapeutic target for mitophagy-related diseases, including PH. |
