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-1¦Á were determined. The role of AMP-activated protein kinase (AMPK) was further analyzed by compound C and AMPK knock-down.
Treatments of mitochondrial inhibitors and an uncoupler respectively reduced both the protein level and transactivation activity of HIF-1¦Á in HepG2 cells under normoxia or hypoxia. The mitochondrial dysfunction-repressed HIF-1¦Á protein synthesis was associated with decreased phosphorylations of p70S6K 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-1¦Á expression.
Mitochondrial dysfunctions resulted in reduced HIF-1¦Á protein synthesis through AMPK-dependent manner in HepG2 cells.
Our results provided a mechanism for communication from mitochondria to the nucleus through AMPK-HIF-1¦Á. Mitochondrial function is important for HIF-1¦Á expression in cancer progression.