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  • br Materials and methods br Results

    2021-10-16


    Materials and methods
    Results
    Discussion Numerous studies have identified important roles for HIF-1α in cellular function and dysfunction through its transcriptional activity [4]. A few studies have reported that HIF-1α is translocated to the mitochondria in human and mouse cancer cell lines [10], [11]. Here, we show that a small fraction of HIF-1α associates with the mitochondria in a highly reproducible manner in human non-cancer as well as cancer cell lines after stabilization in response to oxidative stress, including hypoxia and H2O2 treatment. More importantly, we first detected expression of endogenous mtHIF-1α in mouse liver after induction of fibrosis. Besides, HIF-1α translocates to mitochondria in human liver cell line L02 and human liver carcinoma cell line HepG2, indicating that mitochondrial translocation of HIF-1α not only is broadly observed across cell lines but also is likely to be clinically relevant to the progress from liver fibrosis to liver carcinoma. Rane et al. reported that downregulation of miR-199a or hypoxic preconditioning induced HIF-1α association with the mitochondria of rat cardiac myocytes, where it contributed to the maintenance of mitochondrial membrane potential [11]. Given that mtHIF-1α has now been observed in many cell types in vitro and under pathological conditions in vivo, it is possible that mtHIF-1α may be responsible for some of the known functions of HIF-1α. Our results showed that the kinetics of hypoxia-induced accumulation of HIF-1α at the mitochondria varied in the different cell lines investigated. In the human non-cancer cell lines L02 and HUVEC, HIF-1α was detected at the mitochondria within 1 h of hypoxia, but the effect was transient in HUVEC cells. In HeLa cells, mitochondrial HIF-1α was only detectable after 16 h hypoxia. However, the association was sustained for long periods in HeLa, Hep-G2, and HK-2 Dihydrotestosterone australia (up to 40 h). Briston et al. reported that HIF-1α could be detected in mitochondria within 2 h of hypoxia in the HCT116 cell line [10]. Therefore, although HIF-1α translocation to the mitochondria appears to be a common event, its kinetics and magnitude varies in both cancer and non-cancer cells. We speculate that the varying translocation patterns may partially reflect the individual cellular responses to hypoxia. Previous studies indicated that HIF-1α reduces ROS levels via multiple pathways during hypoxia, including: improving the efficiency of complex IV by switching the cytochrome c oxidase subunit COX4-1 to COX4-2; induction of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, the former shunting pyruvate away from the mitochondria and the latter converting pyruvate to lactate; induction of BNIP3, triggering mitochondrial-selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters required for oxidative phosphorylation (reviewed in [31]). Our results here suggest the existence of a new pathway for decreasing ROS, which involves the association of HIF-1α with the mitochondrial outer membrane. We speculate that mtHIF-1α downregulates mitochondrial mRNA production, which inhibits respiratory chain activity (since some components are encoded by mtDNA) and decreases the demand for O2, thereby alleviating the degree of hypoxia and reducing ROS levels. Notably, previous study and ours have proved association of HIF-1α with outer mitochondrial membrane [12]; however, our results showed down regulation of mtDNA encoded mRNA levels in the matrix by ectopic expression of mtHIF-1α, which can’t be explained by the reported mechanism of HIF-1α/mortalin/VDAC1/HK-II [12]. We speculated that an unknown pathway involving downstream factors located in the matrix exists. Johnson et al. has reported that p53, another transcription factor translocating to mitochondria, inhibited mitochondrial translocation of RelA, which recruits to mitochondrial genome and represses mitochondrial gene expression, by binding to heat shock protein Mortalin which facilitates translocation of RelA to mitochondria, thus indirectly regulating mitochondrial transcription [32]. Therefore, it's possible that mtHIF-1α affects mitochondrial transcription through a similar mechanism.