Hypoxia Win 2019 Nobel Prize HYERBARIC CHAMBER

Energy production in multicellular organisms is carried out by the mitochondria and relies on the presence of molecular oxygen (O2). Regulation of oxygen levels in cells is a critical part of the cellular respiration process, and both too much oxygen (hyperoxia) and lack of sufficient oxygen (hypoxia) have negative effects on cell physiology.

A trio of researchers, Gregg Semenza from Johns Hopkins University, William Kaelin from the Dana-Farber Cancer Institute and Harvard Medical School, and Peter Ratcliffe from Oxford University and the Francis Crick Institute, received the 2019 Nobel Prize in Physiology or Medicine for their discoveries on how cells sense and adapt to O2 variations.

What is Hypoxia?

Hypoxia describes a state where a cell, an organ, or a whole organism doesn’t receive enough oxygen.

Since evolution selected an aerobic mechanism to produce energy in animals, the O2 levels need to be tightly controlled and regulated in these organisms. Uncontrolled variation of O2 levels in multicellular organisms leads to serious consequences.

Aerobic energy production is more efficient than anaerobic processes. One glucose molecule can produce 36 ATP molecules through aerobic glycolysis in mitochondria by the Krebs cycle and aerobic respiration. Anaerobic glycolysis (lactic acid fermentation) only produces 2 ATP molecules from one glucose molecule.

Maintaining sufficient availability of ATP is crucial for appropriate cellular functioning, especially in multicellular organisms. Therefore, since O2 is indispensable for ATP generation through aerobic respiration, cells have developed mechanisms to sense and control the O2 feed, and in particular to sense and respond to hypoxia.

What Happens to Cells During Hypoxia?

Under hypoxic conditions, mitochondria respiration processes generate reactive oxygen species (ROS) due to the reduced efficiency of electron transfer (Chandel NS. et al., 1998). ROS are active molecules that can bind to macromolecules, including DNA, and damage them, resulting in cellular damage or cell death.

Hypoxia can be generalized or local, and its duration can be chronic, acute, or intermittent.

Generalized hypoxia can happen at high altitudes where atmospheric O2 pressure is lower than at sea level. This can lead to “altitude sickness” which causes symptoms such as fatigue, weakness, and nausea. People accustomed to lower elevations respond to generalized hypoxia by producing more red blood cells, which helps compensate for these symptoms (Kjeldsen K. et al., 1968).

Because of the late development of lung tissue in utero, infants born prematurely also experience generalized hypoxia and are placed in hyperbaric incubators to avoid long term exposure to hypoxia (Kerr M., 1964).

Local hypoxia is associated with localized inappropriate vascularization (ischemia), potentially resulting in coronary artery disease, peripheral arterial disease, or diabetes. Severe local chronic hypoxia can lead to needing organ transplantations, and when localized to limb extremities it can induce tissue cyanosis and necrosis and can require amputation (Campbell WB. et al., 2000).

In diseases such as coronary artery disease, ischemia is provoked by atherosclerotic plaques in coronary arteries. In this case, hypoxia in the heart muscle becomes chronic and leads to the remodeling of collateral blood vessels and/or myocardial infarction (Seiler C. et al., 2014).

If cells acutely suffer from hypoxia, aerobic metabolism will switch to anaerobic metabolism, which is less efficient and associated with lactic acid production. This phenomenon is common in muscles during endurance exercise like long-distance running because muscle cells need a high level of energy quickly. The lactic acid production in muscles during anaerobic respiration leads to muscle soreness if not eliminated (Horita T., et al., 1996).

Individuals with obstructive sleep apnea are subjected to intermittent hypoxia up to dozens of times each night. This activates the sympathetic nervous system and levels of plasmatic catecholamines increase, leading to hypertension (Vranish JR., et al., 2016).

The Role of Hypoxia-Induced Factor 1 (HIF-1) in the Response to Low Oxygen

The Hypoxia-Induced Factor 1 (HIF-1) transcription factor is at the center of the transcriptional response to hypoxia. HIF-1 is composed of HIF-1α and HIF-1β subunits and is expressed in every metazoan organism (Loenarz C. et al., 2011). These two subunits can heterodimerize and bind to DNA.

HIF-1α is the limiting component of the HIF-1 complex and it is therefore responsible for regulating HIF-1 activity (Semenza GL. et al., 1996). HIF-1β is present at higher levels and it also heterodimerizes with other proteins. The interaction between HIF-1α with HIF-1β is regulated by oxygenation conditions.

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