SOD2 in mitochondrial dysfunction and neurodegeneration

Abstract

The brain is a highly metabolically active tissue that critically relies on oxidative phosphorylation as a means for maintaining energy. One result of this process is the production of potentially damaging radicals such as the superoxide anion (O2(-)). Superoxide has the capacity to damage components of the electron transport chain and other cellular constituents. Eukaryotic systems have evolved defenses against such damaging moieties, the chief member of which is superoxide dismutase (SOD2), an enzyme that efficiently converts superoxide to the less reactive hydrogen peroxide (H2O2), which can freely diffuse across the mitochondrial membrane. Loss of SOD2 activity can result in numerous pathological phenotypes in metabolically active tissues, particularly within the central nervous system. We review SOD2's potential involvement in the progression of neurodegenerative diseases such as stroke and Alzheimer and Parkinson diseases, as well as its potential role in "normal" age-related cognitive decline. We also examine in vivo models of endogenous oxidative damage based upon the loss of SOD2 and associated neurological phenotypes in relation to human neurodegenerative disorders.

Keywords: Aging; Free radicals; Mitochondria; Neurodegeneration; Oxidative stress; Superoxide dismutase.

Figure 1. Function of Superoxide dismutatses

Schematic of a cell showing the localization and function of the 3 superoxide dismutase isoforms. SOD1 is primarily localized to the cytosol of the cell (yellow) as well in the intramembrane space of the mitochondria, while SOD3 is secreted to the extracellular space (blue). The SOD2 isoform is specifically localized to the inner mitochondrial matrix at the site of superoxide production from the mitochondrial election transport chain (purple). Shown in this diagram is a representation of molecular oxygen diffusing into the mitochondria where it is converted into superoxide as a byproduct of oxidative phosphorylation. SOD2 converts this damaging agent into hydrogen peroxide where it can diffuse from the mitochondria and be further detoxified to water by antioxidant enzymes such as Catalase (CAT) or Glutathione Peroxidase (GPx) (both in the mitochondria in some cases, as well as in the cell).

Figure 2. Aging and neurodegenerative disorders

A simplistic model of how aging impacts the development of neurodegenerative disorders. As we age, there is a decline in a multitude of interrelated cellular processes, including antioxidant defenses of mitochondria, causing a cascade of functional losses ultimately reaching a threshold for bioenergetic collapse and cell death. On a long enough time scale free from morbidity in other tissues; everyone would eventually see the effects of this functional loss prior to death. Therefore examining the progression and timing of the causes and developing therapies to counteract or maintain functional loss are critical in maintaining healthy brain aging.