Reactive Oxygen Species in the Control of Hypoxia-Inducible Factor-Mediated Gene Expression
Authors: Thomas Kietzmann, Agnes Görlach
DOI / Source: https://doi.org/10.1016/j.semcdb.2005.03.010
Date: 17 May 2005
Reading level: Advanced
Why This Matters for Freedivers
Hard breath-holds create a cycle of low oxygen followed by rapid re-oxygenation at the surface, which is exactly the kind of situation that can increase “reactive oxygen species” (ROS). This review helps you understand when ROS are simply damaging “oxidative stress” and when they’re actually signals that switch on longer-term adaptation pathways (like HIF), which matters for how you think about recovery, training frequency, and stacking intense sessions.
Synopsis
ROS (reactive oxygen species) have a bad reputation because high levels can damage proteins, DNA, and cell membranes. But this review makes the modern point: small, controlled ROS bursts are also normal signaling tools. Cells use them to sense stress and adjust gene expression—especially when oxygen levels change.
The paper focuses on the HIF system (hypoxia-inducible factors), the master switch for oxygen-related gene programs. HIF is a transcription factor that turns on many survival and adaptation genes when oxygen is limited. The key is that HIF is mostly controlled after it’s made: under normal oxygen (normoxia) the HIF-α subunit gets chemically “tagged” (hydroxylated), which allows the VHL system to label it for rapid destruction. Under low oxygen (hypoxia), those hydroxylation reactions slow down, HIF-α survives, joins its partner subunit, and activates hypoxia-response genes.
Where ROS comes in is the messy part—and the paper is very honest that this is still debated. The authors summarize evidence that ROS can influence HIF through multiple routes: - Redox control of HIF activity: certain redox-sensitive steps affect how well HIF binds DNA and recruits helper proteins needed for strong gene activation. - Hydroxylase enzymes (PHDs and FIH): these are the “oxygen-dependent tagging” enzymes that control HIF stability and activity. Because they require iron and other cofactors, shifts in redox balance (and antioxidants like ascorbate) can change their function. - Kinase signaling pathways: ROS can activate signaling cascades (like PI3K/Akt and MAPKs) and also inhibit phosphatases, which can indirectly increase HIF signaling even when oxygen is not low.
The paper also walks through the big argument about where ROS under hypoxia comes from. Some experiments suggest hypoxia lowers ROS production (less oxygen available means fewer oxygen radicals), while others suggest hypoxia can increase ROS (especially via mitochondrial electron “traffic jams” that leak electrons). The authors conclude that results vary with cell type, measurement methods, oxygen levels, and timing—and that ROS can either support or limit HIF signaling depending on context.
Overall, this is a “systems” review: it doesn’t claim one simple answer. Instead, it maps out how ROS can act as both a threat and a messenger, and how that feeds into HIF—the gene-control system most linked to hypoxia adaptation.
Abstract
Reactive oxygen species (ROS) have long been considered as cytotoxic. However, recent evidence indicates a prominent role of ROS as signaling molecules in the response to hormones, growth and coagulation factors, cytokines and other factors as well as to changes in oxygen tension. The hypoxia-inducible transcription factors (HIFs) are key players in the cellular response to changes in oxygen tension. Recently, HIFs have also been shown to respond to the above-mentioned non-hypoxic stimuli. In this article, the role of ROS in the regulation of HIF-1 under hypoxic and non-hypoxic conditions is summarized.