Superoxide has been shown to be critically involved in several pathological manifestations of aging animals. In contrast, superoxide also can act as a signaling molecule to modulate signal transduction cascades required for hippocampal synaptic plasticity. Mitochondrial superoxide dismutase (SOD-2 or Mn-SOD) is a key antioxidant enzyme that scavenges superoxide. Thus, SOD-2 may not only prevent aging-related oxidative stress, but may also regulate redox signaling in young animals. We used transgenic mice overexpressing SOD-2 to study the role of mitochondrial superoxide in aging, synaptic plasticity, and memory-associated behavior. We found that overexpression of SOD-2 had no obvious effect on synaptic plasticity and memory formation in young mice, and could not rescue the age-related impairments in either synaptic plasticity or memory in old mice. However, SOD-2 overexpression did decrease mitochondrial superoxide in hippocampal neurons, and extended the lifespan of the mice. These findings increase our knowledge of the role of mitochondrial superoxide in physiological and pathological processes in the brain.
Reactive oxygen species (ROS) include superoxide, hydrogen peroxide, hydroxyl radicals, and unstable intermediates derived from the peroxidation of lipids. ROS have been shown to play important roles as both cellular messenger molecules in physiological events, such as activity-dependent synaptic plasticity and memory (Droge, 2002, Forman et al., 2002, Martindale and Holbrook, 2002, Oury et al., 1999 and Stone and Yang, 2006), and toxic molecules in pathological events, such as ischemia, brain injury, and age-related cell damage (Esposito et al., 2004, Finkel and Holbrook, 2000, Fukagawa, 1999 and Pratico, 2002). Thus, ROS can be both beneficial and deleterious to neuronal function, with the balance between ROS and antioxidants critical for maintaining normal neuronal function.
Superoxide dismutases (SODs) are a class of oxidoreductases that remove superoxide from organisms by catalyzing the dismutation of the superoxide radical to hydrogen peroxide. The resulting hydrogen peroxide is metabolized to molecular oxygen and water by either catalase or glutathione peroxidase (Fridovich, 1995, Marklund, 1984 and Petersen et al., 2003). SODs are a crucial part of the cellular antioxidant defense mechanism (Muscoli et al., 2003). In mammals, there are three different SOD genes encoding three different enzymes. These SOD isozymes catalyze the same chemical reaction, but display different enzymatic properties and distinct cellular localizations. SOD-1 (Cu/Zn-SOD) is found mainly in intracellular compartments; SOD-2 (also referred to as Mn-SOD) is localized primarily in the mitochondrial matrix; and extracellular SOD (EC-SOD), which is usually found in the extracellular space, but can also be found in intracellular vesicle-like structures and on cell surfaces (Oury et al., 1999).
Mitochondrial respiration is a major source of intracellular ROS production (Liu, Fiskum, & Schubert, 2002). Under physiological conditions, approximately 0.2% of oxygen consumption is converted to ROS in and around mitochondria (Staniek and Nohl, 2000 and St-Pierre et al., 2002). Under conditions of altered cellular metabolism, mitochondrial generation of ROS may even be considerably higher (Albers & Beal, 2000). As a consequence, mitochondria are enriched with antioxidants in order to tightly regulate those free radicals (Zeevalk, Bernard, Song, Gluck, & Ehrhart, 2005). SOD-2 or is the major antioxidant enzyme that controls the release of mitochondrial superoxide (Weisiger & Fridovich, 1973) and therefore, is important for mitochondrial superoxide-regulated physiological and pathological events.
It has been reported that two different lines of SOD-2 homozygous knockout mice die shortly after birth (Li et al., 1995 and Lebovitz et al., 1996), whereas overexpression of SOD-2 extends the lifespan of flies (Sun et al., 2002 and Sun et al., 2004) and attenuates drug-induced neurotoxicity in mice (Callio et al., 2005, Klivenyi et al., 1998 and Maragos et al., 2000). However, questions concerning the neurological effects of chronic SOD-2 overexpression over the lifetime of an animal have yet to be addressed.
Our recent work on another SOD isozyme, extracellular SOD (EC-SOD), revealed that EC-SOD overexpression improves hippocampal synaptic plasticity and memory-related behavioral performance in aged mice (Hu, Serrano, Oury, & Klann, 2006). In light of our observations with EC-SOD transgenic mice, we utilized SOD-2 overexpressing mice to examine the role of mitochondrial superoxide on hippocampal function during aging. We found that SOD-2 overexpression decreased mitochondrial superoxide levels, but had no obvious impact on hippocampal LTP and memory in either young or aged mice. However, similar to the previous findings in flies, SOD-2 overexpression extended the lifespan of mice. We conclude that although mitochondrial superoxide may not contribute to age-related impairments in hippocampal synaptic plasticity and memory, decreasing the levels of mitochondrial superoxide in mice increases their longevity.
