Abstract
Oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a major role in the antioxidant system and they also catalyze superoxide radicals (O2•−). Since the loss of cytoplasmic SOD (SOD1) resulted in aging-like phenotypes in several types of mouse tissue, SOD1 is essential for the maintenance of tissue homeostasis. To clarify the cellular function of SOD1, we investigated the cellular phenotypes of Sod1-deficient fibroblasts. We demonstrated that Sod1 deficiency impaired proliferation and induced apoptosis associated with O2•− accumulation in the cytoplasm and mitochondria in fibroblasts. Sod1 loss also decreased the mitochondrial membrane potential and led to DNA damage-mediated p53 activation. Antioxidant treatments effectively improved the cellular phenotypes through suppression of both intracellular O2•− accumulation and p53 activation in Sod1-deficient fibroblasts. In vivo experiments revealed that transdermal treatment with a vitamin C derivative significantly reversed the skin thinning commonly associated with the upregulated p53 action in the skin. Our findings revealed that intrinsic O2•− accumulation promoted p53-mediated growth arrest and apoptosis as well as mitochondrial disfunction in the fibroblasts.
Highlights
Reactive oxygen species (ROS) are mainly generated from mitochondrial respiration and they non- oxidize cellular molecules including proteins, nucleic acid, and lipids, resulting in oxidative damage in organisms [1]
In order to investigate the biological significance of the SOD1 enzyme in cells, we analyzed the cellular phenotypes of Sod1-deficient primary dermal fibroblasts
Positive cells (Figure 1E,F), indicating the induction of apoptotic cell death. These results demonstrated that Sod1 deficiency induced proliferative decline and apoptosis in dermal fibroblasts
Summary
Reactive oxygen species (ROS) are mainly generated from mitochondrial respiration and they non- oxidize cellular molecules including proteins, nucleic acid, and lipids, resulting in oxidative damage in organisms [1]. ROS dysregulates mitochondrial function through a reduction of membrane potential and respiration [3] In this context, maintenance of redox balance in cells plays an important role in the determination of cellular fate and function, including apoptosis, cell cycle arrest, differentiation, and energy metabolism [4]. Several groups have reported that Sod1−/− deficiency induced: hepatocellular carcinoma [13], muscle atrophy [14], hemolytic anemia [15] in mice, and poor growth rate in cells [16]. These observations indicate that Sod1−/− mice have the potential to be a valuable animal model for investigating human age-related diseases
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