Over-expression of microRNA-494 up-regulates hypoxia-inducible factor-1 alpha expression via PI3K/Akt pathway and protects against hypoxia-induced apoptosis

The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53.

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Interleukin-1β promotes hypoxia-induced apoptosis of glioblastoma cells by inhibiting hypoxia-inducible factor-1 mediated adrenomedullin production

Cell Death and Disease ◽

10.1038/cddis.2013.562 ◽

2014 ◽

Vol 5 (1) ◽

pp. e1020-e1020 ◽

Cited By ~ 17

Author(s):

W Sun ◽

R Depping ◽

W Jelkmann

Keyword(s):

Hypoxia Inducible Factor ◽

Interleukin 1Β ◽

Glioblastoma Cells ◽

Hypoxia Inducible Factor 1 ◽

Induced Apoptosis

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HIF-1αhad Pivotal Effects on Downregulation of miR-210 Decreasing Viability and Inducing Apoptosis in Hypoxic Chondrocytes

The Scientific World JOURNAL ◽

10.1155/2014/876363 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Zhiqiang Chang ◽

Lifeng Huo ◽

Yimin Wu ◽

Pei Zhang

Keyword(s):

Hypoxia Inducible Factor ◽

Regulatory Mechanisms ◽

Human Chondrocytes ◽

Positive Role ◽

Hypoxia Inducible Factor 1 ◽

Qrt Pcr ◽

Induced Apoptosis ◽

First Time

Hypoxia-inducible factor 1-alpha (HIF-1α) and some microRNA (miRNAs) play pivotal roles in response to hypoxia-related physiologic and pathophysiologic responses. Up to date, the regulatory mechanisms of these molecules were largely unknown in chondrocytes. In this study, to study the mechanisms of degradation and homeostasis of chondrocytes, the effects of miRNAs and HIF-1αon chondrocytes in physiologic environment were investigated. We found that the overexpression of miR-210 and HIF-1αwas present on hypoxia in C28/I2 human chondrocytes significantly by qRT-PCR and western plot. Further study displayed that miR-210 played positive role as a promoter in regulation and its regulated molecules (bcl-xl and PHD-2) in C28/I2 cells on hypoxia by silenced miR-210, silenced HIF-1α, and adding miR-210. Moreover, downregulated miR-210 could significantly repress the viability and increase the apoptosis in C28/I2 cells on hypoxia, compared to those on normoxia. Furthermore, miR-210 could not modulate viability and apoptosis in C28/I2 cells with the HIF-1αknockdown on hypoxia and normoxia. Taken together, this study demonstrated that the MiR-210 was involved in an HIF-1α-dependent way in C28/I2 human chondrocytes for the first time. It also suggested that miR-210 downregulation decreased viability and induced apoptosis in hypoxic chondrocytes depending on HIF-1α.

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