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

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.