title: Mortalin-mediated and ERK-controlled targeting of HIF-1α to mitochondria confers resistance to apoptosis under hypoxia.
abstract: Hypoxia inducible factor-1 (HIF-1) is the main transcriptional activator of the cellular response to hypoxia and an important target of anticancer therapy. Phosphorylation by ERK1 and/or ERK2 (MAPK3 and MAPK1, respectively; hereafter ERK) stimulates the transcriptional activity of HIF-1α by inhibiting its CRM1 (XPO1)-dependent nuclear export. Here, we demonstrate that phosphorylation by ERK also regulates the association of HIF-1α with a so-far-unknown interaction partner identified as mortalin (also known as GRP75 and HSPA9), which mediates non-genomic involvement of HIF-1α in apoptosis. Mortalin binds specifically to HIF-1α that lacks modification by ERK, and the HIF-1α-mortalin complex is localized outside the nucleus. Under hypoxia, mortalin mediates targeting of unmodified HIF-1α to the outer mitochondrial membrane, as well as association with VDAC1 and hexokinase II, which promotes production of a C-terminally truncated active form of VDAC1, denoted VDAC1-ΔC, and protection from apoptosis when ERK is inactivated. Under normoxia, transcriptionally inactive forms of unmodified HIF-1α or its C-terminal domain alone are also targeted to mitochondria, stimulate production of VDAC1-ΔC and increase resistance to etoposide- or doxorubicin-induced apoptosis. These findings reveal an ERK-controlled, unconventional and anti-apoptotic function of HIF-1α that might serve as an early protective mechanism upon oxygen limitation and promote cancer cell resistance to chemotherapy.
authors.affiliation: Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece.
authors.forename: Ilias
authors.identifier: 0000-0002-0893-6618
authors.initials: I
authors.lastname: Mylonis
authors.affiliation: Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Kourti
authors.affiliation: Biomedical Sciences Research Center (B.S.R.C.) "Alexander Fleming", 34 Fleming Street, 16672 Vari, Greece.
authors.forename: Martina
authors.initials: M
authors.lastname: Samiotaki
authors.affiliation: Biomedical Sciences Research Center (B.S.R.C.) "Alexander Fleming", 34 Fleming Street, 16672 Vari, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Panayotou
authors.affiliation: Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece simos@med.uth.gr.
authors.forename: George
authors.identifier: 0000-0001-5453-3185
authors.initials: G
authors.lastname: Simos
mesh_terms: D017209:Apoptosis; D015687:Cell Hypoxia; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D000072417:Protein Domains; D021381:Protein Transport; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C494762:VDAC1 protein, human; C080352:mortalin; D049452:Green Fluorescent Proteins; D050995:Voltage-Dependent Anion Channel 1; D006593:Hexokinase; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Apoptosis; ERK; HIF-1; Hypoxia; Mitochondria; Mortalin