Abstract
Energy metabolism and redox state are strictly linked; energy metabolism is a source of reactive oxygen species (ROS) that, in turn, regulate the flux of metabolic pathways. Moreover, to assure redox homeostasis, metabolic pathways and antioxidant systems are often coordinately regulated. Several findings show that superoxide dismutase 1 (SOD1) enzyme has effects that go beyond its superoxide dismutase activity and that its functions are not limited to the intracellular compartment. Indeed, SOD1 is secreted through unconventional secretory pathways, carries out paracrine functions and circulates in the blood bound to lipoproteins. Striking experimental evidence links SOD1 to the redox regulation of metabolism. Important clues are provided by the systemic effects on energy metabolism observed in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). The purpose of this review is to analyze in detail the involvement of SOD1 in redox regulation of metabolism, nutrient sensing, cholesterol metabolism and regulation of mitochondrial respiration. The scientific literature on the relationship between ALS, mutated SOD1 and metabolism will also be explored, in order to highlight the metabolic functions of SOD1 whose biological role still presents numerous unexplored aspects that deserve further investigation.
Highlights
As a result of normal cellular metabolism, cells continuously produce several types of reactive oxygen species (ROS) including superoxide anions, hydrogen peroxide, hydroxyl radicals, and a variety of their reaction products like organic hydroperoxides and hypochlorous acid [1]
Interesting data show that rapamycin treatment, inhibiting mechanistic target-of-rapamycin complex 1 (mTORC1), increases the orexigenic Agrp mRNA levels in cells exposed to high amino acid concentration; these observations indicate that amino acids can act within the brain to inhibit food intake and that a direct, mTOR-dependent inhibition of AGRP gene expression may contribute to this effect [96]
Ghrelin and leptin exert opposite regulatory effects on feeding behavior and metabolism acting on POMC and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC); their effects are mediated by mTORC1 activity [90,94], suggesting that mTORC1 may serve as a switch mechanism able to mediate the diverse role of these two hormones in the regulation of food intake [93]
Summary
As a result of normal cellular metabolism, cells continuously produce several types of reactive oxygen species (ROS) including superoxide anions, hydrogen peroxide, hydroxyl radicals, and a variety of their reaction products like organic hydroperoxides and hypochlorous acid [1]. Cellular metabolism generates ATP through mitochondrial electron transport chain (ETC) During these reactions, small amounts of oxygen superoxide radical (O2−), the principal ROS formed in mitochondria, are physiologically produced by addition of one electron to molecular oxygen. Relevant amount of ROS are generated by membrane-bound NADPH oxidase enzymes (NOX) that produce oxygen radicals through one electron reduction of molecular oxygen using NAD(P)H molecules as electron donors [21]. Because H2O2 is designated to be the major redox signaling molecule, it is more dangerous than O2− when produced in an excessive/non-controlled amount For these reasons, the physiological and pathological effects of these molecules depend on the amount and on their intracellular site of generation [36]. Sci. 2020, 21, 6606 water and molecular oxygen, while GSH-Px and GSH-Reductase reduce H2O2 to water and/or lipid peroxides to their corresponding alcohols, at the expense of this low-molecular-weight thiol [43]
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