Key Laboratory of Transplant Engineering and Immunology of The Ministry of Health, Regenerative Medicine Research Centre, The Organ Transplantation Centre, West China Hospital, Sichuan University, Chengdu 610041, China.
Key Laboratory of Transplant Engineering and Immunology of The Ministry of Health, Regenerative Medicine Research Centre, The Organ Transplantation Centre, West China Hospital, Sichuan University, Chengdu 610041, China.
Redox Biol. 2019 Jul;25:101109. doi: 10.1016/j.redox.2019.101109. Epub 2019 Jan 14.
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 HO treatment. Moreover, the livers of mice with CCl-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 HO-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 HO 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来介导对氧化应激的适应性反应。线粒体的变化对于对氧化应激的适应性反应至关重要。然而，HIF-1α 调节线粒体以响应氧化应激的转录和非转录机制尚不清楚。在这里，我们检查了人细胞中 HIF-1α 的亚细胞定位，并确定了一小部分 HIF-1α 在暴露于缺氧或 HO 处理后易位到线粒体。此外，CCl 诱导的纤维化小鼠的肝脏显示出 HIF-1α 与线粒体结合的逐渐增加，表明这一发现具有临床相关性。为了探究这部分 HIF-1α 的功能，我们过表达了一种线粒体靶向形式的 HIF-1α（mito-HIF-1α）。mito-HIF-1α 的表达足以减轻暴露于缺氧或 HO 诱导的氧化应激引起的细胞凋亡。此外，mito-HIF-1α 的表达独立于核途径减少了对缺氧或 HO 处理的反应性氧物种的产生、线粒体膜电位的崩溃以及线粒体 DNA 编码 mRNA 的表达。这些数据表明，线粒体 HIF-1α 独立于其作为转录因子的众所周知的作用，可防止氧化应激诱导的细胞凋亡。
