Mark Wefers Bettink

Mind the mitochondria! 2 25 acetaminophen were decreased significantly during hypoxia. At the same time Na + /K + pump activity, an essential process for maintaining cell ion homeostasis was maintained. No lactate production was measured during prolonged moderate hypoxia which supports the finding that cellular ATP demand was down-regulated by the reduction of non-essential metabolic processes. Later studies also described oxygen conformance in other cell types such as skeletal muscle (25) and chick cardiomyocytes (26). The mechanism of oxygen conformance is only partly known. Cytochrome c oxidase (complex 4), the terminal electron acceptor in the electron transport chain, is reversibly inhibited after expose to low oxygen concentration ( < 50 mM) for several hours (27). It has been suggested that cytochrome C oxidase could act as an oxygen sensor as its reduction state has an effect on its kinetic activity (28) and hence oxygen consumption by the cell. A later study in cardiomyocytes confirmed this mechanism (29). The mechanism involved in the subsequent reduction in ATP as described by Subramanian is less clear. It might involve a difference in ATP affinity of ATP consuming proteins (24). Alternatively AMPK, a kinase that maintains a balance between cellular ATP generation and consumption could be involved (30). It has been shown that AMPK becomes activated during hypoxia and is dependent on mitochondrial complex III (31). It is expected that other causes of ATP reduction, like mitochondrial dysfunction, activate similar pathways to reduce ATP demand. Hits on mitochondria Next to their role in cellular adaptation and the more indirect downregulation of mitochondrial respiration, mitochondria are also directly susceptible to certain “hits” that cause mitochondrial damage and dysfunction as part of pathophysiology and treatment. Unfortunately, mitochondrial (dys)function is difficult to measure in the ward and as a consequence there is little clinical awareness of its occurrence. However, general goals in medicine, such as securing oxygen supply, starting therapy for infectious disease, treating cancer, performing an operation and securing comfort during the operation are likely to influence mitochondrial function. For example, acute changes in mitochondrial function might be a cornerstone in the development of SIRS or sepsis. The accompanying mitochondrial dysfunction might be caused by a combination of hyperoxia/hypoxia, medication and inflammation-induced metabolic changes, as shown in figure 1. A short overview of possible hits on mitochondria follows.