Abstract
Abstract Background and Aims Mitophagy activation is crucial for hypoxia signaling in acute kidney injury (AKI). Selective removal of damaged mitochondria is mediated through a concerted function of coding and non-coding RNA expressions. Insights on HIF-1α signaling in lncRNA-regulated mitophagy mechanism are not known. The study aims to investigate the role of hypoxia-inducible factor 1α (HIF-1α) regulated long non-coding RNA (lncRNA) ATP6V0E2-AS1 in acute kidney injury (AKI) by examining its effect on mitophagy. Method Mitophagy proteins (PINK1, p-PARKIN, LC3) were determined through western blot analysis. Immunofluorescence studies of PINK1 mitochondrial translocation and LC3/TOMM20 localization were determined using confocal analysis. HIF-1α interaction with lncRNA-ATP6V0E2-AS1 through promoter binding activity was evaluated through chromatin immunoprecipitation analysis. RNA interaction between lncRNA-ATP6V0E2-AS1 and PINK1 was analyzed by dual-luciferase reporter assay. Results Hypoxia upregulated PINK1, p-PARKIN, LC3 expressions, and mitophagosome in HK-2 cells. Overexpression and knockdown studies of hypoxia-regulated lncRNA-ATP6V0E2-AS1 significantly regulated PINK1/p-PARKIN expressions, subsequent PINK1 mitochondrial co-localization, and mitophagosome formation. shHIF-1α knockdown in HK-2 cells reveals that HIF-1α mediates PINK1/p-PARKIN mitophagy regulation under hypoxic conditions. In detail, HIF-1α binds to the promoter of lncRNA-ATP6V0E2-AS1 and down-regulates its expression under hypoxia. Deficiency of both HIF-1α and lncRNA-ATP6V0E2-AS1 reverted shHIF-1α mediated suppression of PINK1 expression and mitophagosome formation. Further, ATP6V0E2-AS1 post-transcriptionally regulates PINK1 expression by RNA-RNA interaction. Conclusion Altogether, our study shows novel findings on the HIF-1α mediated lncRNA-ATP6V0E2-AS1 in hypoxia-induced mitophagy regulation in the renal tubular cells. Thus, downregulated ATP6V0E2-AS1 expression with subsequent mitophagy activation is critical for hypoxia-induced mitophagy regulation through HIF-1α/ATP6V0E2-AS1/PINK1 axis.
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