HIF-1α protects against oxidative stress by directly targeting mitochondria

• Main Authors: Hong-Sheng Li, Yan-Ni Zhou, Lu Li, Sheng-Fu Li, Dan Long, Xue-Lu Chen, Jia-Bi Zhang, Li Feng, You-Ping Li
• Format: Article
• Language: English
• Published: Elsevier 2019-07-01
• Series: Redox Biology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213231718308127

The transcription factor hypoxia inducible factor-1α (HIF-1α) mediates adaptive responses to oxidative stress by nuclear translocation and regulation of gene expression. Mitochondrial changes are critical for the adaptive response to oxidative stress. However, the transcriptional and non-transcriptional mechanisms by which HIF-1α regulates mitochondria in response to oxidative stress are poorly understood. Here, we examined the subcellular localization of HIF-1α in human cells and identified a small fraction of HIF-1α that translocated to the mitochondria after exposure to hypoxia or H2O2 treatment. Moreover, the livers of mice with CCl4-induced fibrosis showed a progressive increase in HIF-1α association with the mitochondria, indicating the clinical relevance of this finding. To probe the function of this HIF-1α population, we ectopically expressed a mitochondrial-targeted form of HIF-1α (mito-HIF-1α). Expression of mito-HIF-1α was sufficient to attenuate apoptosis induced by exposure to hypoxia or H2O2-induced oxidative stress. Moreover, mito-HIF-1α expression reduced the production of reactive oxygen species, the collapse of mitochondrial membrane potential, and the expression of mitochondrial DNA-encoded mRNA in response to hypoxia or H2O2 treatment independently of nuclear pathways. These data suggested that mitochondrial HIF-1α protects against oxidative stress induced-apoptosis independently of its well-known role as a transcription factor. Keywords: Mitochondria, HIF-1α, Oxidative stress, Apoptosis, ROS