Mark Wefers Bettink

Mind the mitochondria! 2 23 other biochemically relevant molecules. The ground state is a triplet state that has the important implication that molecular oxygen does not react directly with many other molecules, in contrast to the highly reactive oxygen radical singlet oxygen. The adequate supply of oxygen to organs and tissues is of pivotal importance to sustain mammalian life. Aerobic metabolism is maintained through inhalation of air in the lungs and subsequent transport of the absorbed oxygen to tissues via the circulating blood. The flow of hemoglobin-bound oxygen through the macro- andmicrocirculation and diffusion of molecular oxygen into the tissue cells brings oxygen to its ultimate destination, the mitochondria. In the mitochondria, oxygen is used in oxidative phosphorylation in order to efficiently produce adenosine triphosphate (ATP) that acts as the energy source for many cellular processes. Oxygen also plays a role in many other biochemical processes and mammalian tissue contains a large number of oxygen-consuming enzymes (7), for example for reactive oxygen species generation in signal transduction (8,10). Cellular hypoxia causes mitochondrial dysfunction, oxidative damage, activation of inflammatory cascades and complement activation, ultimately leading to tissue death. If oxygenation is restored after a prolonged period of time hypoxia, re-oxygenation injury, or ischemia-reperfusion injury, occurs which leads to augmented oxidative stress and tissue injury (11,12). In this respect it is interesting to note that it is actually unknown, or ill-defined, what “hypoxia” actually is. For example, from a medical point of view one could define hypoxia as a pathological condition in which the body or a region of the body is deprived of an adequate oxygen supply. But the question here obviously is: what does adequate mean in this respect? In the classical view, cellular respiration is unaffected by oxygen levels until PO 2 decreases below 2 to 3 mmHg (13-16) . This is because of the high affinity of the mitochondrial respiratory chain for oxygen. In the more modern view, oxygen availability is directly influencing cellular metabolism and function by processes like oxygen conformance and cellular metabolic reprogramming, processes that appear to occur at much higher oxygen levels (see below). So, while in the classical view hypoxia is almost equivalent to anoxia, in the modern view any perturbation from a current PO 2 level could alter mitochondrial respiration and ultimately cellular function. Therefore, the actions of medical doctors to achieve “adequate tissue oxygenation” might in the end, unintentionally, alter cellular metabolism and function due to alterations in tissue oxygen levels, e.g., by superfluous oxygen administration or vasopressor therapy (17).