HIF-1? protects against oxidative stress by directly targeting mitochondria.

ABSTRACT: The transcription factor hypoxia inducible factor-1? (HIF-1?) 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-1? regulates mitochondria in response to oxidative stress are poorly understood. Here, we examined the subcellular localization of HIF-1? in human cells and identified a small fraction of HIF-1? 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-1? association with the mitochondria, indicating the clinical relevance of this finding. To probe the function of this HIF-1? population, we ectopically expressed a mitochondrial-targeted form of HIF-1? (mito-HIF-1?). Expression of mito-HIF-1? was sufficient to attenuate apoptosis induced by exposure to hypoxia or H₂O₂-induced oxidative stress. Moreover, mito-HIF-1? 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-1? protects against oxidative stress induced-apoptosis independently of its well-known role as a transcription factor.

SUBMITTER: Li HS 

PROVIDER: S-EPMC6859547 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature