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Biochim Biophys Acta. 2013 Oct;1830(10):4743-51. doi: 10.1016/j.bbagen.2013.06.004. Epub 2013 Jun 18.

Mitochondrial dysfunction represses HIF-1α protein synthesis through AMPK activation in human hepatoma HepG2 cells.

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  • 1Department and Institute of Pharmacology, National Yang-Ming University, Taiwan.

Abstract

BACKGROUND:

Hypoxia-inducible factor-1α (HIF-1α) is an important transcription factor that modulates cellular responses to hypoxia and also plays critical roles in cancer progression. Recently, somatic mutations and decreased copy number of mitochondrial DNA (mtDNA) were detected in hepatocellular carcinoma (HCC). These mutations were shown to have the potential to cause mitochondrial dysfunction. However, the effects and mechanisms of mitochondrial dysfunction on HIF-1α function are not fully understood. This study aims to explore the underlying mechanism by which mitochondrial dysfunction regulates HIF-1α expression.

METHODS:

Human hepatoma HepG2 cells were treated with various mitochondrial respiration inhibitors and an uncoupler, respectively, and the mRNA and protein expressions as well as transactivation activity of HIF-1α were determined. The role of AMP-activated protein kinase (AMPK) was further analyzed by compound C and AMPK knock-down.

RESULTS:

Treatments of mitochondrial inhibitors and an uncoupler respectively reduced both the protein level and transactivation activity of HIF-1α in HepG2 cells under normoxia or hypoxia. The mitochondrial dysfunction-repressed HIF-1α protein synthesis was associated with decreased phosphorylations of p70(S6K) and 4E-BP-1. Moreover, mitochondrial dysfunction decreased intracellular ATP content and elevated the phosphorylation of AMPK. Treatments with compound C, an AMPK inhibitor, and knock-down of AMPK partially rescued the mitochondrial dysfunction-repressed HIF-1α expression.

CONCLUSIONS:

Mitochondrial dysfunctions resulted in reduced HIF-1α protein synthesis through AMPK-dependent manner in HepG2 cells.

GENERAL SIGNIFICANCE:

Our results provided a mechanism for communication from mitochondria to the nucleus through AMPK-HIF-1α. Mitochondrial function is important for HIF-1α expression in cancer progression.

Copyright © 2013 Elsevier B.V. All rights reserved.

KEYWORDS:

AMP-activated protein kinase; AMPK; Adenosine monophosphate-activated protein kinase; CAIX; CCCP; DMEM; Dulbecco's modified Eagle medium; HCC; HIF-1α; Hypoxia-inducible factor-1α; LDHA; Mitochondrial dysfunction; Protein synthesis; ROS; RT-PCR; carbonic anhydrase IX; carbonyl cyanide m-chlorophenyl hydrazine; hepatocellular carcinoma; hypoxia-inducible factor-1α; lactate dehydrogenase A; mitochondrial DNA; mtDNA; reactive oxygen species; reverse transcription-polymerase chain reaction

PMID:
23791554
[PubMed - indexed for MEDLINE]
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