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First published online August 6, 2004
Journal of Experimental Biology 207, 3171-3188 (2004)
Published by The Company of Biologists 2004
doi: 10.1242/jeb.01075

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Cellular oxygen sensing need in CNS function: physiological and pathological implications

Till Acker^1,2,* and Helmut Acker³

¹ Karolinska Institute, Cellular and Molecular Biology, Stockholm, Sweden
² Edinger Institute, Frankfurt, Germany
³ Max Planck Institute for Molecular Physiology, Dortmund, Germany

View larger version (51K): [in a new window]   Fig. 1. Dual role of HIF in regulating cell survival and cell death, depending on PO2 and HIF- protein levels. The HIF system transactivates an extended physiological pathway, encompassing a wide array of physiological responses to hypoxia, ranging from mechanisms that increase cell survival to those inducing cell cycle arrest or even apoptosis. Depending on the degree and duration of hypoxia, quantitative and qualitative changes in the hypoxia response occur that may be regulated by concomitant changes in HIF- protein levels, modifications and HIF- subunit expression.

View larger version (75K): [in a new window]   Fig. 2. HIF-1 localization in brain under physiological and pathophysiological conditions. (A) Heterogeneity of nuclear HIF-1 localization in neurons of the mouse cortex under physiological conditions is probably related to the heterogeneous distribution of tissue PO2. In addition, HIF- expression may be influenced by other factors discussed, such as PHD activity or growth factor signaling. (B) In contrast, human brain tumors show distinct nuclear HIF-1 localization in pallisading cells close to the necrotic core (N) of glioblastoma multiforme.

View larger version (36K): [in a new window]   Fig. 3. Modulation of oxygen sensor sensitivity by cofactors. Oxygen-sensing systems connecting an oxygen-dependent enzymatic activity to the regulation of hypoxia-inducible responses should operate at high and low PO2 affinities, fitting the heterogeneous PO2 distribution curve. Oxygen-sensing heme proteins such as mitochondrial complex IV (cytochrome c oxidase) and NAD(P)H-oxidase as well as PHD have been described as candidate sensor systems functioning at different Km values. Modulation of the specific PO2 affinities or oxygen sensor activities would allow efficient triggering and fine-tuning of various signal cascades to optimize cellular function and adaptation over a broad range of O2 concentrations.

View larger version (33K): [in a new window]   Fig. 4. N2 versus aerobic steady state spectrum (black solid noisy line) as a mean of six carotid bodies fitted by different mitochondrial and non-mitochondrial cytochrome spectra, indicated by different colors. The superposition curve (black solid line) obtained by varying the amplitude of the optical density of five cytochromes closely fits the experimental curve (Streller et al., 2002).

View larger version (99K): [in a new window]   Fig. 5. Three-dimensional 2-photon confocal laser scanning microscopy (2P-CLSM) of PHD1, PHD2, PHD3 and FIH-1. Different EGFP fluorescence intensities of single cells are visualized in false colors as indicated by the color bar. Up to 64 optical slices through transfected cells were recovered by 2P-CLSM. After reconstruction of the optical slices the distribution of the EGFP fluorescence within a single cell is 3D-visualized. A cut through the cell reveals the inside distribution. Overlays of all the optical slices are shown in the inserts (Metzen et al., 2003).

View larger version (19K): [in a new window]   Fig. 6. Oxygen-sensing synopsis under (A) normoxia and (B) hypoxia. In normoxia, HIF- is constitutively synthesized and sent to proteosomal destruction, controlled by PHD-dependent hydroxylation. In addition, NAD(P)H oxidase as the major donor of ROS has been implicated in controlling HIF- stability, potentially involving the iron-mediated Fenton reaction. Reduced O2 levels in hypoxia result in stabilization of HIF- and subsequent HIF-target gene expression due to declining O2-dependent PHD and NAD(P)H oxidase activity. Further, during hypoxic events mitochondria have been suggested to be the major source of ROS formation at complex III, aiding HIF- stabilization. In addition, as a consequence of the declining mitochondrial membrane potential, an impaired cytosolic calcium buffering dominates, which triggers transmitter release or ion channel conductivity eliciting a hypoxic cellular response. Not all ROS-mediated pathways on HIF activity are part of an oxygen-signaling response but rather expression of a delicate integration of oxygen-sensing mechanisms into major growth factor signaling pathways.