Oxygen sensing strategies in mammals and bacteria

Abstract

The ability to sense and adapt to changes in pO2 is crucial for basic metabolism in most organisms, leading to elaborate pathways for sensing hypoxia (low pO2). This review focuses on the mechanisms utilized by mammals and bacteria to sense hypoxia. While responses to acute hypoxia in mammalian tissues lead to altered vascular tension, the molecular mechanism of signal transduction is not well understood. In contrast, chronic hypoxia evokes cellular responses that lead to transcriptional changes mediated by the hypoxia inducible factor (HIF), which is directly controlled by post-translational hydroxylation of HIF by the non-heme Fe(II)/αKG-dependent enzymes FIH and PHD2. Research on PHD2 and FIH is focused on developing inhibitors and understanding the links between HIF binding and the O2 reaction in these enzymes. Sulfur speciation is a putative mechanism for acute O2-sensing, with special focus on the role of H2S. This sulfur-centered model is discussed, as are some of the directions for further refinement of this model. In contrast to mammals, bacterial O2-sensing relies on protein cofactors that either bind O2 or oxidatively decompose. The sensing modality for bacterial O2-sensors is either via altered DNA binding affinity of the sensory protein, or else due to the actions of a two-component signaling cascade. Emerging data suggests that proteins containing a hemerythrin-domain, such as FBXL5, may serve to connect iron sensing to O2-sensing in both bacteria and humans. As specific molecular machinery becomes identified, these hypoxia sensing pathways present therapeutic targets for diseases including ischemia, cancer, or bacterial infection.

Keywords: Cysteine; FNR; FixL; HIF; Hypoxia; Oxygen sensing.

Figure 1. Proposed mechanism for ion channel O₂ sensing in NEBs

NADPH oxidase mediates the hypoxic response in NEBs via O₂^- or H₂O₂.

Figure 2. Acute hypoxia sensing in mammalian tissues

Acute hypoxia causes inhibition of K⁺ channels in type 1 glomus cells and NEBs. The depolarization increases intracellular [Ca²⁺], leading to neurotransmitter release and improved ventilation. In systemic SMCs, acute hypoxia causes K_ATP channels to open, inhibiting calcium influx and causing vasodilation. Inhibition of K⁺ channels in pulmonary artery SMCs causes depolarization and calcium influx that results in vasoconstriction.

Figure 3. H₂S production and oxidation in the cytosol and mitochondria

Key compounds are cysteine (Cys), homocysteine (hCys), methionine (Met), and glutathione persulfide (GSSH).

Figure 4. Regulation of HIF-1α by FIH and PHD2

Posttranslational regulation of HIF-1α by FIH and PHD2 control HIF-1α transcriptional activity and stability under normoxic conditions. During hypoxia, HIF-1α forms a transcription complex with HIF-1β and p300, and initiates target gene expression.

Figure 5

Proposed consensus mechanism of the αKG-dependent hydroxylases.

Figure 6. O₂ sensing by FNR

A) FNR protein domain arrangement. B) FNR [Fe₄S₄]²⁺ cluster degradation. In the presence of O₂, the FNR [Fe₄S₄]²⁺ cofactor is rapidly oxidized to [Fe₂S₂]²⁺, leading to dissociation of dimeric FNR. Reconstitution of the [Fe₄S₄]²⁺ cluster in FNR occurs through the Isc pathway in vivo, but can also be reconstituted in vitro by exogenous Fe²⁺ and DTT [111].

Figure 7

A) Protein crystal structure of the heme binding PAS domain of FixL from B. japonicum in the unliganded Fe³⁺ oxidation state (PDB 1LSW) [134], with the conformationally mobile FG loop labelled in black. B) The heme active site of BjFixL. Hydrogen bond interactions to the heme propionate groups have a significant role in shifting the FG loop conformation for oxy-FixL, slowing autophosphorylation [124, 133-135, 150-152]. C) Protein constructs of BjFixL, ReFixL and SmFixL. The empty N-terminal PAS domain likely tunes O₂ affinity and influences signal transduction [153-156].