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.

转录因子缺氧诱导因子-1α（HIF-1α）通过核易位和基因表达的调节介导对氧化应激的适应性反应。线粒体变化对于氧化应激的适应性反应至关重要。但是，人们对HIF-1α响应氧化应激调节线粒体的转录和非转录机制了解甚少。在这里，我们检查了人类细胞中HIF-1α的亚细胞定位，并发现了暴露于低氧或H ₂ O ₂处理后转移到线粒体中的一小部分HIF-1α 。此外，CCl ₄小鼠的肝脏诱导的纤维化显示HIF-1α与线粒体的相关性逐渐增加，表明该发现具有临床意义。为了探究该HIF-1α群体的功能，我们异位表达了HIF-1α的线粒体靶向形式（mito-HIF-1α）。mito-HIF-1α的表达足以减弱由于暴露于缺氧或H ₂ O ₂引起的氧化应激诱导的细胞凋亡。此外，mito-HIF-1α的表达减少了活性氧的产生，线粒体膜电位的降低以及线粒体DNA编码的缺氧或H ₂ O ₂响应的mRNA的表达。治疗独立于核途径。这些数据表明线粒体HIF-1α不受氧化应激诱导的细胞凋亡的影响，而与其作为转录因子的众所周知的作用无关。