How Cells Overcome Oxidative Stress

At some point in the evolutionary past, living organisms began to use molecular oxygen in cellular respiratory metabolic pathways and therefore gained access to increased amounts of energy to support life.  This was especially important in the evolution of complex multi-cellular organisms.    Along with this new capability came the issue of dealing with the harmful by-products of oxidative respiration.  The most detrimental of these are reactive oxygen species (ROS) that are produced in the mitochondria – those organelles that generate most of the energy required for cellular processes within eukaryotic cells.

ROS can produce oxidative damage and have been shown to be involved in a number of serious human pathologies including Alzheimer’s, cancer, diabetes and Parkinson’s.  These reactive molecular species are also involved in cellular senescence and cell death.

In response to this threat - referred to as oxidative stress - cells have developed mechanisms designed to minimize the damage.   the ROS defense system localized in the mitochondria transforms highly reactive and potentially destructive superoxide anions (O₂^--)  to hydrogen peroxide (H₂O₂) that is subsequently broken down to water by ubiquitous peroxidase enzymes that use reduced glutathione (GSH) as their substrate.  Given the essential role that GSH plays in this mechanism, it is crucial that appropriate levels of this substance are maintained.   A key enzyme that is employed in providing high levels of GSH is the nicotinamide nucleotide transhydrogenase (TH) enzyme.

Dr. Leung and his colleagues at the Department of Integrative Structure and Computational Biology at the Scripps Research Institute in La Jolla CA studied the three dimensional structure of TH and elucidated its mechanism of action.  This kind of information is important in so far as it increases the overall understanding of how cells cope with oxidative stress.