Reactive oxygen species, nutrition, hypoxia and diseases: Problems solved?

Abstract

Within the last twenty years the view on reactive oxygen species (ROS) has changed; they are no longer only considered to be harmful but also necessary for cellular communication and homeostasis in different organisms ranging from bacteria to mammals. In the latter, ROS were shown to modulate diverse physiological processes including the regulation of growth factor signaling, the hypoxic response, inflammation and the immune response. During the last 60-100 years the life style, at least in the Western world, has changed enormously. This became obvious with an increase in caloric intake, decreased energy expenditure as well as the appearance of alcoholism and smoking; These changes were shown to contribute to generation of ROS which are, at least in part, associated with the occurrence of several chronic diseases like adiposity, atherosclerosis, type II diabetes, and cancer. In this review we discuss aspects and problems on the role of intracellular ROS formation and nutrition with the link to diseases and their problematic therapeutical issues.

Keywords: Diabetes; Diets; Diseases; Free radicals; Hypoxia; Metabolism; Mitochondria; Obesity; Oxygen.

Graphical abstract

Fig. 1

ROS generation in cells. ROS can be generated in response to various stimuli among them diets or radiation which is supported by the action(s) of enzyme(s) located in different intracellular compartments. ETC, electron transport chain;

Fig. 2

Interrelation between ROS in signaling and cell damage. ROS generated in cells by specific action of various enzymes appear to have a more critical role in signaling than ROS generated as by-products of intracellular processes or due to external toxic stimuli. ETC, electron transport chain. PDH, pyruvate dehydrogenase; KGDH, α-ketoglutarate dehydrogenase.

Fig. 3

ROS-regulated signaling pathways. Simplified diagram representing major ROS regulated signaling pathways. ROS can influence the pathways either positively or negatively; see text for further explanations. ROS necessary for regulation of signaling pathways are mostly generated through specific enzymatic reactions as well as due to the changes in cellular metabolic activity leading to altered ROS production. DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GP, G-protein; GPCR, G-protein coupled receptor; Grb2, growth factor receptor-bound protein 2; HIF-1α, hypoxia-inducible factor-1α; IκB, inhibitor of NF-κB; IKK, IκB kinase; MEK, MAPK/ERK kinase; MKP3, mitogen-activated protein (MAP) kinase phosphatase/dual specificity protein phosphatase-6; PHD, prolyl hydroxylase; PI3K, phosphatidylinositol 3-kinases; PI3P, phosphatidylinositol 3-phosphate; PKB/Akt, protein kinase B; PKC, protein kinase C; PTEN, phosphatase and tensin homolog deleted on chromosome 10; Raf, ras attachement factor; Ras, Rat sarcoma; RTK, receptor tyrosine kinase; SOS, son of sevenless; Shc, SHC-transforming protein; Src, sarcoma. ETC, electron transport chain; NF-κB, nuclear factor kappa B; NOX, NADPH oxidase subunit; PKC, protein kinase C; PPAR, peroxisome proliferator-activated receptor; SOD, superoxide dismutase; TCA, tricarboxylic acid.

Fig. 4

Nutrients modulate ROS generation. Nutrients (free fatty acids, glucose, amino acids) stimulate ROS production by increasing the postprandial metabolic rate, especially in mitochondria. Further, nutrients affect ROS via signal cascades and transcription factors that regulate expression of antioxidant/ROS-generating enzymes.

Fig. 5

ROS generation and nutrient availability. Under nutrient-deficient conditions, as well as in the presence of nutrient excess ROS formation is above the physiological threshold. As such, these conditions may be considered as pathological situations, with abnormally high ROS generation.