Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice

Abstract

Oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative disorders such as Parkinson's and Alzheimer's disease. However, it is not yet understood how endogenous mitochondrial oxidative stress may result in mitochondrial dysfunction. Most prior studies have tested oxidative stress paradigms in mitochondria through either chemical inhibition of specific components of the respiratory chain, or adding an exogenous insult such as hydrogen peroxide or paraquat to directly damage mitochondria. In contrast, mice that lack mitochondrial superoxide dismutase (SOD2 null mice) represent a model of endogenous oxidative stress. SOD2 null mice develop a severe neurological phenotype that includes behavioral defects, a severe spongiform encephalopathy, and a decrease in mitochondrial aconitase activity. We tested the hypothesis that specific components of the respiratory chain in the brain were differentially sensitive to mitochondrial oxidative stress, and whether such sensitivity would lead to neuronal cell death. We carried out proteomic differential display and examined the activities of respiratory chain complexes I, II, III, IV, V, and the tricarboxylic acid cycle enzymes alpha-ketoglutarate dehydrogenase and citrate synthase in SOD2 null mice in conjunction with efficacious antioxidant treatment and observed differential sensitivities of mitochondrial proteins to oxidative stress. In addition, we observed a striking pattern of neuronal cell death as a result of mitochondrial oxidative stress, and were able to significantly reduce the loss of neurons via antioxidant treatment.

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…Bcl-2 prevents activation of caspases involved in apoptosis, including caspase-3 and -9, by inhibition of cytochrome c release and by binding to apoptotic protease activating factor 1 (Murphy, 1999). SOD2, is a mitochondrial enzyme that protects against superoxide radicals that are normal by-products of cellular metabolism but can produce cell damage (Hinerfeld et al, 2004).…”

“…Activation of ERK1/2, CREB, and NF-κB can enhance anti-apoptic actions by inducing expression of anti-apoptotic Bcl-2 proteins and antioxidant enzymes such as manganese superoxide dismutase (SOD2) that protect against superoxide radicals (Hetman and Gozdz, 2004;Hinerfeld et al, 2004;Martinou et al, 1994;Mattson et al, 1997;Mattson and Meffert, 2006). The increased levels of ERK1/2, CREB, and NF-κB coupled with the increased levels of the neuronal protein enolase and glial protein GFAP suggested that these downstream neuroprotective proteins could also be altered by chronic CXCL10.…”

Absence of superoxide dismutase activity causes nuclear DNA fragmentation during the aging process

“…In Caenorhabditis elegans, deletion of SOD genes leads to unexpected results; absence of SOD2 gene causes an increase and simultaneous deletion of all five SOD genes causes no shortage in the lifespan [15]. It has been reported that Drosophila null mutations for either the cytoplasmic Cu/ZnSOD or the mitochondrial MnSOD greatly decreases viability and the life span [16], however in mice only SOD2 mutation has a severe effect [17,18]. Thus, regulation of the life span by SODs is a controversial issue in different organisms and further characterization of SOD deficient cells needs to be performed to understand the ambiguities regarding their regulatory roles in the life span.…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…Free radicals and reactive oxygen species (ROS) have been reported for their contribution to neuronal loss in cerebral ischemia, seizure disorders, schizophrenia, PD and AD (Floyd and Carney, 1992;Good et al, 1996;Christen, 2000;Barja, 2004;Hinerfeld et al, 2004). A growing body of evidences implicates oxidative stress as being involved in the propagation of cellular injury that leads to neuropathology in these various conditions (Good et al, 1996;Christen, 2000;Andersen, 2004).…”

“…Neurons are considered to be more susceptible to oxidative damage as compared to cells in other tissues (Barja, 2004;Gille et al, 2004;Hinerfeld et al, 2004). ROS can initiate a cascade of reactions that leads to neuronal cell death (Floyd and Carney, 1992;Berlett and Stadtmann, 1997;Uttara et al, 2009).…”