Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging

Abstract

Manganese superoxide dismutase (MnSOD or SOD2) is a key mitochondrial enzymatic antioxidant. Arguably the most striking phenotype associated with complete loss of SOD2 in flies and mice is shortened life span. To further explore the role of SOD2 in protecting animals from aging and ageassociated pathology, we generated a unique collection of Drosophila mutants that progressively reduce SOD2 expression and function. Mitochondrial aconitase activity was substantially reduced in the Sod2 mutants, suggesting that SOD2 normally ensures the functional capacity of mitochondria. Flies with severe reductions in SOD2 expression exhibited accelerated senescence of olfactory behavior as well as precocious neurodegeneration and DNA strand breakage in neurons. Furthermore, life span was progressively shortened and age-dependent mortality was increased in conjunction with reduced SOD2 expression, while initial mortality and developmental viability were unaffected. Interestingly, life span and age-dependent mortality varied exponentially with SOD2 activity, indicating that there might normally be a surplus of this enzyme for protecting animals from premature death. Our data support a model in which disruption of the protective effects of SOD2 on mitochondria manifests as profound changes in behavioral and demographic aging as well as exacerbated age-related pathology in the nervous system.

Biomarkers to identify and isolate senescent cells

“…ROS increase with age and correlate with many age-related cellular changes (Liochev, 2013). Furthermore, elements associated with protection against oxidative stress (Cox2, SOD, Mn and other antioxidants) often show reduced functionality in aged organisms (Espinoza et al, 2008;Paul et al, 2007).…”

Mitochondrial Superoxide Radicals Differentially Affect Muscle Activity and Neural Function

“…KG06854R is a precise excision revertant stock of a P-element insertion in the Sod2 gene and therefore used as a control in all experiments because it shares a similar genetic background with Sod2 n283 (Paul et al 2007). MHC (myosin heavy chain)-Gal4, Mef-2 (myocyte enhancer factor-2) GAL4, Tub (tubulin)-Gal4, Elav (embryonic lethal abnormal vision)-Gal4, and UAS-lacZ flies were obtained from the Drosophila Stock Center in Bloomington, Indiana.…”

“…Western blotting and histochemical analyses: Western analysis with Drosophila SOD2 (Stressgen, San Diego) and actin (Abcam, Cambridge, MA) antibody was done essentially as described previously in Paul et al (2007). For b-galactosidase staining cryosections were stained with X-gal substrate (Wolff 2000).…”

“…Assuming that superoxide itself is not enough to affect the functionality of the neurons when SOD is absent, it might also explain our earlier claim that precocious neurodegeneration was observed in a Sod2 wk / Sod2 n283 (Sod2 weak/null) situation where SOD2 activity has been reduced to $22% (Paul et al 2007). It is en-tirely possible that such a basal level of SOD2 activity was sufficient to convert enough superoxides into H 2 O 2 and hydroxyl radicals and thereby cause neurodegeneration.…”

“…The severe phenotypic effects of SOD2 loss of function have been attributed to elevated DNA damage and protein carbonylation (Golden and Melov 2001). SOD2 loss of function has also been attributed to ''free radical attack'' or ''oxidative insult'' on mitochondria where obvious mitochondrial damage was apparent from the inactivation of mitochondrial Fe-S cluster enzymes aconitase and succinate dehydrogenase (Melov et al 1999;Kirby et al 2002;Paul et al 2007). Furthermore, impairment of cellular signaling, specifically those induced by reactive oxygen species (ROS) (Klotz 2005), might also play a very significant role in the early mortality effects of SOD2-deficient flies as indicated recently (Wicks et al 2009).…”