Hypoxia, defined as the deficiency of oxygen in the biotic environment, causes cellular stress and alters normal metabolic activity. Exposure to hypoxia causes an increased accumulation of reactive oxygen species (ROS) and leads to oxidative stress, which can have damaging effects on a vast array of cellular components. Cells have adapted intracellular signaling mechanisms in response to hypoxia to maintain viability. These pathways have a net effect of reducing overall metabolic rates to allow cells to survive and recover during bouts of low oxygen. In particular, hypoxia is a common feature of many solid tumors as their increased growth exceeds their blood supply, rendering areas of the tumor with significantly lower oxygen concentration compared to surrounding healthy tissue.
Definition of 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 increased production of reactive oxygen species (ROS).
- Buildup of ROS results in a state known as oxidative stress, the imbalance between the production of ROS and the cell’s antioxidant defenses. Excess ROS can cause damage to all cellular components including lipids, proteins, and DNA.
- 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 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.
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.