Reactive oxygen species and cellular oxygen sensing

Abstract

Many organisms activate adaptive transcriptional programs to help them cope with decreased oxygen levels, or hypoxia, in their environment. These responses are triggered by various oxygen sensing systems in bacteria, yeast and metazoans. In metazoans, the hypoxia inducible factors (HIFs) mediate the adaptive transcriptional response to hypoxia by upregulating genes involved in maintaining bioenergetic homeostasis. The HIFs in turn are regulated by HIF-specific prolyl hydroxlase activity, which is sensitive to cellular oxygen levels and other factors such as tricarboxylic acid cycle metabolites and reactive oxygen species (ROS). Establishing a role for ROS in cellular oxygen sensing has been challenging since ROS are intrinsically unstable and difficult to measure. However, recent advances in fluorescence energy transfer resonance (FRET)-based methods for measuring ROS are alleviating some of the previous difficulties associated with dyes and luminescent chemicals. In addition, new genetic models have demonstrated that functional mitochondrial electron transport and associated ROS production during hypoxia are required for HIF stabilization in mammalian cells. Current efforts are directed at how ROS mediate prolyl hydroxylase activity and hypoxic HIF stabilization. Progress in understanding this process has been enhanced by the development of the FRET-based ROS probe, an vivo prolyl hydroxylase reporter and various genetic models harboring mutations in components of the mitochondrial electron transport chain.

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

“…Reactive oxygen species (ROS) is another factor implicated in HIF1A accumulation. Evidence suggests that ROS increases HIF1A by directly inhibiting PHD catalytic activity (Cash et al 2007, Kaelin & Ratcliffe 2008. Finally, reports have also suggested that hypoxia can act independently of the HIF1A transcription factor (Bindra et al 2005, Arany et al 2008, Fujisaka et al 2013.…”

Development of ascorbate transporters in brain cortical capillary endothelial cells in culture

“…Salnikow, et al (Salnikow et al, 2005) have proposed that divalent cations such as cobalt and nickel increase HIF-1α protein by oxidizing and thus depleting cellular ascorbate. Ascorbate is the preferred electron donor to the prolyl-4-hydoxylase (EC 1.14.11.2) that is responsible for hydroxylating HIF-1α, which then targets it for destruction in the ubiquitin-proteosome system (Cash et al, 2007). Without ascorbate, this hydroxylation would not occur and HIF-1α would accumulate.…”

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

“…However, the importance of ROS either as therapeutic, cytotoxic molecule or as signaling molecule under the different oxygen conditions in a tumor and its specific relevance for the outcome to therapy are not clear. In fact, it has been convincingly demonstrated that ROS levels either increase or decrease under hypoxic conditions 364,365,[371][372][373] . These contradictory effects have been associated with differences in the methodological approaches, in the cell types investigated, in the metabolic state of the cells, in the disease context, and so on.…”

“…However, none of these latter methods is specific for a certain type of ROS. In addition, ROS can also be determined in frozen tissues by staining with the fluorescent dyes such as DCF or DHE 364,372,373 . However, to date, the most specific approach to detect superoxide anion radicals and other free radicals intra-or extracellularly is based on electron spin resonance (ESR).…”