Hypoxia—the deficiency of oxygen in the cellular environment—causes cellular stress and alters normal metabolic activity. Under hypoxic conditions,the accumulation of reactive oxygen species (ROS) leads to oxidative stress, which can damage a wide array of cellular components. To maintain viability, cells have adapted intracellular signaling mechanisms that reduce overall metabolic rates, allowing survival and recovery during periods of low oxygen.
Hypoxia is a common feature of many solid tumors. In cancerous tissue, the rapid growth of tumors can exceed the available blood supply, resulting in regions with significantly lower oxygen concentrations than surrounding healthy tissue.
What is hypoxia?
Hypoxia is a pathophysiological condition caused by a deficiency in oxygen (O2) due to an imbalance between cellular O2 consumption and vascular perfusion. Under hypoxic conditions, limited oxygen molecules are available to serve as final electron acceptors in the electron transport chain, leading to the increased production of reactive oxygen species (ROS). The resulting oxidative stress reflects an imbalance between ROS generation and the cell’s antioxidant defenses, leading to potential damage to lipids, proteins, and DNA.
Related Blog: Hypoxia and Cancer: The role of HIF-1α in oxygen sensing, metabolism, and tumorigenesis
Cells adapt to hypoxia by activating specialized hypoxia response pathways, which downregulate metabolic activity to avoid overwhelming the bioenergetic machinery. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that serves as a master regulator of the cellular hypoxia response pathways by coordinating a decrease in electron chain transport activity and downregulating protein translation and Na-K-ATPase activity.
Immunofluorescent analysis of HepG2 cells, untreated (left) or exposed to hypoxia-mimetic conditions with cobalt chloride (500 μM, 24 h; right), using HIF-1α (D1S7W) XP® Rabbit mAb #36169 (green). Nuclear accumulation of HIF-1α in CoCl₂-treated cells confirms hypoxia pathway activation. Actin filaments were labeled with DyLight™ 554 Phalloidin #13054 (red).
What are reactive oxygen species?
Reactive oxygen species (ROS) are highly reactive oxidant molecules and free radicals derived from molecular oxygen. ROS are normal by-products of ATP generation via electron transport in mitochondria and have important roles in cell signaling and cellular homeostasis.
In healthy cells, ROS toxicity is kept in check by intracellular antioxidant systems including catalase, glutathione, and superoxide dismutase (SOD). When cells are stressed, as is the case under hypoxic conditions, ROS accumulate, resulting in oxidative stress.
Excess ROS has damaging effects of cellular components including damage of DNA or RNA, oxidation of amino acids, lipid peroxidation, and oxidative deactivation of enzymatic activity.
