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.cell death | endogenous tolerance | fluorescence lifetime imaging microscopy-FRET | mitochondria | preconditioning B alanced energy metabolism and regulation of apoptosis are of vital importance to all organisms (1, 2). Therefore, energy metabolism and regulation of apoptosis are interdependent (3). In cells, metabolism and apoptosis converge at mitochondria, thereby integrating pathways responsible for endogenous tolerance against substrate deprivation (4). All differentiated multicellular organisms have evolved strategies to promote survival when deprived of metabolic substrates, such as during hypoxia (5). Therefore, elucidating the underlying molecular mechanisms by which metabolism and apoptosis are coregulated may lead to novel therapeutic strategies for both acute and chronic diseases.The transcription factor hypoxia-inducible factor (HIF)-1 is a key regulator in the adaptation to hypoxia and the resultant energy depletion, orchestrating the cellular response to hypoxic conditions (5-7). Induction of HIF-1 leads to the transcriptional regulation of a multitude of genes, ultimately resulting in a hypoxia-tolerant state of the cell (7). HIF-1 also links hypoxia and glycolysis (8) via complex and incompletely understood mechanisms. HIF-1 adapts cellular metabolism to hypoxic conditions during development (7) or exercise (9) and thereby prevents death of tumor cells and primary cells under various conditions of disease (5-7, 10). In addition, HIF-1 controls innate immunity by regulating glycolysis in cells of the immune system (11, 12). Finally, by controlling the expression of members of the glycolytic cascade, including hexokinase II (HKII) (7, 8), HIF-1 contributes to a proliferative metabolism (13).Mitochondrial glycolytic h...
Beta-cell apoptosis and failure to induce beta-cell regeneration are hallmarks of type 2-like diabetes in mouse models. Here we show that islets from obese, diabetes-susceptible New Zealand Obese (NZO) mice, in contrast to diabetes-resistant C57BL/6J (B6)-ob/ob mice, do not proliferate in response to an in-vivo glucose challenge but lose their beta-cells. Genome-wide RNAseq based transcriptomics indicated an induction of 22 cell cycle-associated genes in B6-ob/ob islets that did not respond in NZO islets. Of all genes differentially expressed in islets of the two strains, seven mapped to the diabesity QTL Nob3, and were hypomorphic in either NZO (Lefty1, Apoa2, Pcp4l1, Mndal, Slamf7, Pydc3) or B6 (Ifi202b). Adenoviral overexpression of Lefty1, Apoa2, and Pcp4l1 in primary islet cells increased proliferation, whereas overexpression of Ifi202b suppressed it. We conclude that the identified genes in synergy with obesity and insulin resistance participate in adaptive islet hyperplasia and prevention from severe diabetes in B6-ob/ob mice.
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