Mark Wefers Bettink

Chapter 2 22 species (ROS). Mitochondria-generated ROS were originally considered potentially toxic by-products, but are now considered to be key signaling molecules in various (patho) physiological processes. For example, mitochondrial ROS at low levels causes metabolic adaptation in hypoxia while high levels of mitochondrial ROS activate apoptosis (3) and autophagy (4). Thus,mitochondrial ROSareassociatedwithprocesses ranging fromcellular adaptation to inducing cell death. Also, mitochondrial ROS are involved in regulating the inflammatory response and can be stimulated by danger signals. An example is the activation of Toll-like receptors (5) by bacterial ligands such as lipopolysaccharide (6). While most mitochondrial oxygen consumption is used for generating ATP, mitochondrial oxidative metabolism is not limited to ATP generation. As stated above, a small amount of oxygen consumed is directed toward ROS production. Furthermore, a certain amount of respiration is uncoupled from ATP production and lost as heat (7) and used for thermogenesis (8). The amount of mitochondrial coupling varies from tissue to tissue and is typically high in heart and much lower in liver and skeletal muscle (9). Specific uncoupling proteins within the inner mitochondrial membrane use the mitochondrial membrane potential for thermogenesis and are present in e.g. brown adipocytes. Next to functions linked to the respiratory chain, recent discoveries point to a much broader role of mitochondria in cell homeostasis. For example, mitochondria possess a calcium uniporter (10,11)and might play a role in intracellular calcium homeostasis (12). Also, while mitochondria are essential in sustaining life, they play a major role in (programmed) cell death. Opening of the mitochondrial permeability transition pore, as a result of a stressful stimulus such as calcium or ROS overload, leads to loss of the mitochondrial membrane potential (13). The collapse of the membrane potential results in ATP depletion and necrosis (14), and the release of mitochondrial content such as cytochrome c leads to apoptosis (15). The role of oxygen Molecular oxygen is a diatomic gas that constitutes approximately 21% of the volume of air. The electron configuration of the oxygen molecule has two unpaired electrons with the same spin in degenerate orbitals. Therefore, oxygen is paramagnetic and the ground state of oxygen is a triplet state, which is very unusual compared to many