HIF-1 prevents the overproduction of mitochondrial ROS after cytokine stimulation through induction of PDK-1.
Excessive reactive oxygen species (ROS) are toxic to hematopoietic cells. The majority of cellular ROS are derived from mitochondria and glucose metabolism, and cytokines stimulate this process. During hypoxia, hypoxia inducible factor-1 (HIF-1) attenuates hypoxia-induced mitochondrial ROS production through the induction of pyruvate dehydrogenase kinase-1 (PDK-1). Previously, we found that thrombopoietin (TPO) induces the generation of mitochondrial ROS. Interestingly, the TPO-induced production of mitochondrial ROS promotes the activation of HIF-1. Based on these findings, we speculated that TPO-activated HIF-1 functions as a feedback mechanism to block the overproduction of ROS following TPO stimulation. We found that TPO induces the expression of PDK-1 in a TPO-dependent cell line, UT-7/TPO, in a HIF-1-dependent manner. Inhibition of either HIF-1 or PDK-1 resulted in the increased production of ROS following TPO stimulation. Our observations suggest that HIF-1 functions as a ROS sensor to prevent the overproduction of mitochondrial ROS following cytokine stimulation.
Kirito
Keita
K
Department of Hematology/Oncology, University of Yamanashi, Chuo, Yamanshi, Japan. kirito@yamanashi.ac.jp
Hu
Yongzhen
Y
Komatsu
Norio
N
D005246:Feedback; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013926:Thrombopoietin / Q000494:pharmacology*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013926:Thrombopoietin; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D017346:Protein Serine-Threonine Kinases