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

• Published in: Redox biology Vol. 25; p. 101109
• Main Authors: Li, Hong-Sheng, Zhou, Yan-Ni, Li, Lu, Li, Sheng-Fu, Long, Dan, Chen, Xue-Lu, Zhang, Jia-Bi, Feng, Li, Li, You-Ping
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2019; Elsevier
• Subjects: Animals; Apoptosis; Cell Hypoxia; Cell Line; Cytoprotection; DNA, Mitochondrial - genetics; Down-Regulation; HIF-1α; Humans; Hydrogen Peroxide - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Oxidative Stress; Protein Transport; RNA, Messenger - genetics; RNA, Messenger - metabolism; ROS; Transcription, Genetic; DMOG; WCL; Oxidative stress; MT-COII; TOMM40; PCNA; mtDNA; PARP; HO-1; HIF-1α; CTAD; PHD; NTAD; MT-ND1; HIF-1; Mitochondria; TMRM; ΔΨm; TIMM17A; HUVEC; ID; GSH; AIF; SOD2; ROS; CAT; HA; TFAM; nDNA; MT-CYB; GAPDH; HDAC; NFE2L2; Apoptosis
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101109

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.
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•HIF-1α is recruited to mitochondria in response to oxidative stress.•Mitochondrial HIF-1α protects against oxidative stress induced apoptosis.•HIF-1α in mitochondria reduces ROS levels and reverses mitochondrial damage.•Mitochondrial HIF-1α reduces mtDNA encoded mRNA levels.•Mitochondrial HIF-1α may involve in liver fibrosis.