title: Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state.
abstract: The metabolic state of a cell is a key determinant in the decision to live and proliferate or to die. Consequently, balanced energy metabolism and the regulation of apoptosis are critical for the development and maintenance of differentiated organisms. Hypoxia occurs physiologically during development or exercise and pathologically in vascular disease, tumorigenesis, and inflammation, interfering with homeostatic metabolism. Here, we show that the hypoxia-inducible factor (HIF)-1-regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. We provide evidence for a direct molecular interactor of HKII and show that, together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation. HKII both protects cells from death during hypoxia and functions as a sensor of glucose availability during normoxia, inducing apoptosis in response to glucose depletion. Thus, HKII-mediated apoptosis may represent an evolutionarily conserved altruistic mechanism to eliminate cells during metabolic stress to the advantage of a multicellular organism.
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. philipp.mergenthaler@charite.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Mergenthaler
authors.forename: Anja
authors.initials: A
authors.lastname: Kahl
authors.forename: Anne
authors.initials: A
authors.lastname: Kamitz
authors.forename: Vincent
authors.initials: V
authors.lastname: van Laak
authors.forename: Katharina
authors.initials: K
authors.lastname: Stohlmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Thomsen
authors.forename: Heiko
authors.initials: H
authors.lastname: Klawitter
authors.forename: Ingo
authors.initials: I
authors.lastname: Przesdzing
authors.forename: Lars
authors.initials: L
authors.lastname: Neeb
authors.forename: Dorette
authors.initials: D
authors.lastname: Freyer
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Collins
authors.forename: Dirk
authors.initials: D
authors.lastname: Megow
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000378:metabolism*; D002384:Catalysis; D019070:Cell Lineage; D006593:Hexokinase / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats
chemical_list: D051017:Apoptosis Regulatory Proteins; C490443:Pea15 protein, rat; D010750:Phosphoproteins; D006593:Hexokinase