Nitric oxide (NO) is a gaseous signalling molecule that is synthesised by nitric oxide synthases (NOSs) and has a variety of physiological and pathophysiological roles. Some of its physiological functions are primarily mediated via the activation of soluble guanylate cyclase. However, NO is also able to potently inhibit mitochondrial respiration at complex IV of the electron transport chain (ETC) in a manner that is reversible and in competition with oxygen (O2). Following prolonged exposure to NO, the ETC undergoes an NO-dependent modification at complex I, which results in a persistent inhibition of respiration. Activated macrophages were found to produce NO, via upregulation of the inducible isoform of NOS (iNOS), in sufficient quantities to inhibit respiration. This inhibition was initially reversible but became persistent with time. In addition, haem oxygenase-1 (HO-1) is upregulated in these cells, producing carbon monoxide (CO), which is also known to inhibit complex IV. The ability of exogenous and endogenous CO to inhibit respiration was investigated. Although less potent than NO, CO was shown to cause significant inhibition of respiration, particularly under hypoxic (1% O2) conditions. Furthermore, hypoxia was found to attenuate significantly the synthesis of NO from iNOS but not CO from HO-1. The consequences of inhibition of respiration were investigated under hypoxia, where the availability of O2 may be limiting for O2-dependent cellular processes. Specifically, the effects of respiratory inhibition were investigated with regards to the stability of hypoxia-induced hypoxia inducible factor la (HTFla). Hypoxia resulted in the stabilisation of HIF1α protein, a phenomenon that was prevented by inhibition of the ETC at various complexes. This destabilisation of HIFla was found to be due to a redistribution of intracellular O2 from mitochondrial consumption, resulting in an increased intracellular O2 concentration and the reactivation of the O2-dependent degradation of HIF1α protein.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:420425 |
| Date | January 2005 |
| Creators | Lam, Francis King Wan |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1444915/ |
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