title: Mitochondrial complex II regulates a distinct oxygen sensing mechanism in monocytes.
abstract: Mutations in mitochondrial complex II (succinate dehydrogenase; SDH) genes predispose to paraganglioma tumors that show constitutive activation of hypoxia responses. We recently showed that SDHB mRNAs in hypoxic monocytes gain a stop codon mutation by APOBEC3A-mediated C-to-U RNA editing. Here, we test the hypothesis that inhibition of complex II facilitates hypoxic gene expression in monocytes using an integrative experimental approach. By RNA sequencing, we show that specific inhibition of complex II by atpenin A5 in normoxic conditions mimics hypoxia and induces hypoxic transcripts as well as APOBEC3A-mediated RNA editing in human monocytes. Myxothiazol, a complex III inhibitor, has similar effects in normoxic monocytes. Atpenin A5 partially inhibits oxygen consumption, and neither hypoxia nor atpenin A5 in normoxia robustly stabilizes hypoxia-inducible factor (HIF)-1α in primary monocytes. Several earlier studies in transformed cell lines suggested that normoxic stabilization of HIF-1α explains the persistent expression of hypoxic genes upon complex II inactivation. On the contrary, we find that atpenin A5 antagonizes the stabilization of HIF-1α and reduces hypoxic gene expression in transformed cell lines. Accordingly, compound germline heterozygosity of mouse Sdhb/Sdhc/Sdhd null alleles blunts chronic hypoxia-induced increases in hemoglobin levels, an adaptive response mainly regulated by HIF-2α. In contrast, atpenin A5 or myxothiazol does not reduce hypoxia-induced gene expression or RNA editing in monocytes. These results reveal a novel role for mitochondrial respiratory inhibition in induction of the hypoxic transcriptome in monocytes and suggest that inhibition of complex II activates a distinct hypoxia signaling pathway in a cell-type specific manner.
authors.affiliation: Department of Pathology.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Cortes Gomez
authors.affiliation: Department of Pathology.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Taggart
authors.affiliation: Department of Pathology.
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D042963:Electron Transport Complex II / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008689:Methacrylates / Q000008:administration & dosage; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage; D017393:RNA Editing / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013844:Thiazoles / Q000008:administration & dosage; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003564:Cytidine Deaminase; D042963:Electron Transport Complex II; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D008689:Methacrylates; D011506:Proteins; D011728:Pyridones; D013385:Succinate Dehydrogenase; D013844:Thiazoles; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C582347:SDHC protein, mouse; C058278:atpenin A5; C030517:myxothiazol; C108095:SDHB protein, human; C574938:SDHD protein, mouse; C121399:APOBEC3A protein, human