Redox Signaling & Disease

Unbalanced levels of reactive oxygen species (ROS) are a common denominator of many acute and chronic degenerative diseases such as atherosclerosis, type II diabetes, acute liver and renal failure as well as neurodegenerative diseases including Parkinson’s and Alzheimer’s disease and stroke. Although previously thought to induce cell death in an unspecific, necrotic manner, recent data has shown that ROS may induce cell death in a highly regulated Caspase-independent fashion (Fig. 1). On the other hand, research in the last years has established that ROS are not only detrimental to cells, but at physiological level regulate a myriad of cellular process including transcription regulation and cell signalling as best studied for receptor tyrosine kinase signalling (Fig. 2).
To dissect the apparently opposing functions of ROS in cell cycle progression and cell death signalling, our laboratory takes advantage of knockout mouse models for key redox enzymes of the glutathione- and thioredoxin-related systems, such as glutathione peroxidases, the cystine/glutamate antiporter and thioredoxin reductase. These models along with inducible knockout cells are powerful tools to perturb cellular redox homeostasis in cells and tissues in a spatiotemporal manner to better understand the mechanisms of stress-induced degenerative diseases as a basis for the development of novel treatment strategies to collectively combat these diseases.

Fig. 1:
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Glutathione and GPx4 sense and translate oxidative stress into a distinct cell death signaling pathway. Low glutathione (GSH) levels, as evident in many neurodegenerative diseases, causes impaired GPx4 function and aberrant 12/15-lipoxygenase (12/15-LOX) activity. Lipid hydroperoxides generated by 12/15-LOX may trigger Bid and apoptosis inducing factor (AIF) activation and neurodegeneration.


Fig. 2:
http://www.helmholtz-muenchen.de/uploads/pics/Group_Conrad_Fig_2.jpg

A novel pathway describing of how lipid hydroperoxides (LOOH) regulate receptor tyrosine kinase (RTK) signaling. (A) The ability of lipid hydroperoxides (15-HPETE) to oxidize protein tyrosine phosphates (PTPs; e.g. SHP-1) in vitro was compared with hydrogen peroxide (H2O2), the well-established inducer of PTP oxidation. (B) The concept of PTP regulation by NADPH oxidase derived H2O2 is shown on the right. Stimulation of the receptor triggers superoxide anion and H2O2 formation and PTP oxidation. Glutathione peroxidase 1 (GPx1) and peroxiredoxin II (PrxII) control H2O2 levels. Recent data shows that lipid hydroperoxides (15-HPETE) generated by 12/15-LOX or possibly by other lipoxygenase isoforms effectively oxidize and inactivate PTP’s (left). As GPx4 reduces peroxidised lipids, GPx4 may be regarded also as an important regulator of RTK signaling.