Oxidative Stress

Oxidative stress refers to the imbalance due to excess reactive oxygen species (ROS) or oxidants over the capability of the cell to mount an effective antioxidant response. ^[1] Reactive oxygen species are derivatives of oxygen molecules generated during aerobic metabolism, and while low levels are required for diverse cellular processes, excess ROS can be pathological and contribute to the development and progression of chronic diseases. ^[2] Oxidative stress results in macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging. ^[1]

Reactive oxygen species are generated during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. ^[1] Paradoxically, accumulating evidence indicates that ROS also serve as critical signaling molecules in cell proliferation and survival, acting on pathways such as MAP kinases, PI3 kinase, PTEN, and protein tyrosine phosphatases. ^[1] Cellular defense against oxidative damage relies on antioxidant systems, including glutathione, a non-enzymatic antioxidant that maintains redox balance and detoxifies reactive oxygen species. ^[3] Reactive cysteines are direct targets of oxidative stress, as reactive oxygen species can modify catalytic cysteine residues required for the enzymatic activity of cysteine proteases such as deubiquitinating enzymes. ^[4]

The appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span. ^[5] In aging, reactive oxygen species stimulate mitochondrial dynamic changes and accelerate the accumulation of oxidized by-products, and imbalanced mitochondrial quality control may accelerate cellular senescence and aging. ^[6] Immune cells maintain an optimal concentration of mitochondrial ROS to sustain physiological responses, and excessive or insufficient mtROS production contributes to chronic inflammation, autoimmunity, and cancer. ^[7]

Despite evidence linking elevated ROS to chronic kidney disease, the use of low-molecular-weight antioxidants to remove ROS has not been successful in preventing or slowing disease progression, and more selective control of specific ROS-mediated signalling pathways is being pursued. ^[2] Low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, whereas high levels promote contractile dysfunction resulting in muscle weakness and fatigue, so interventions capable of protecting muscle from oxidant-mediated dysfunction are being explored. ^[8]