Is Lipid Peroxidation of Polyunsaturated Acids the Only Source of Free Radicals That Induce Aging and Age-Related Diseases?

Abstract

The increase in free radicals is hypothesised to cause aging and age-related diseases. The most common source of free radicals is thought to be superoxide. This superoxide is claimed to be released from mitochondria during the enzymatic transformation of oxygen to water by a "leakage" process. This article presents evidence that leakage does not occur. Instead, protonated superoxide radicals are generated by lipid peroxidation processes. In nature, polyunsaturated fatty acids (PUFAs) represent particularly oxygen-sensitive compounds. Apparently, nature uses this sensitivity for signalling processes by producing lipidhydroperoxides (LOOHs) by any change to cell membrane structure. LOOHs easily undergo further enzymatic transformations to compounds which contribute to activation of genes. Bivalent metal ions within the active site of lipoxygenases catalyse LOOH production. The metal ions generate radicals which are transformed within the enzyme complex to non-radical molecules. Thus radicals never leave the enzyme complex except in severe stress situations. In this case the radical intermediates attack bonds, keeping the metal ion in its complex state. Thus, metal ions are released and react in a Fenton reaction with LOOH molecules produced earlier by lipoxygenase to form LO. radicals. Radicals are typically four orders of magnitude more reactive than non-radical molecules. Their action is not under genetic control, they attack nearly all biological molecules, destroying lipids, proteins, nucleic acids, hormones and enzymes until the radicals are quenched by scavenger molecules. The principal degradation routes are outlined in this review. Lysophospholipids are generated in large amounts after stress by activation of phospholipases and are transformed to LO. radicals. These can abstract a hydrogen radical from a lysophospholipid. The radical thus formed adds oxygen and decomposes to a 2-oxolysophospholipid and a HOO. radical (protonated superoxide). HOO. radicals in turn abstract hydrogen atoms from other molecules and produce H(2)O(2). Since any cell preparation method causes membrane destruction, it is inevitable that protonated superoxide is generated, explaining why H(2)O(2) molecules are found as "byproducts" of many reactions.

Effects of arachidonic acid on the concentration of hydroxyeicosatetraenoic acids in culture media of mesenchymal stromal cells differentiating into adipocytes or osteoblasts

“…In fact, the non-enzymatic peroxidation is a known process (Niki et al 2005), mainly involving unsaturated fats (Spiteller 2010), being further enhanced in our experiments, due to the culture medium incubation in the presence of atmospheric oxygen (21 %). The concentration of the five studied HETE did not significantly change in the three culture media used (basal, adipogenic and osteogenic) after incubation in the presence of AA without cells.…”

Influence of Endodontic Treatment on Systemic Oxidative Stress

“…This hyperbaric therapy was subsequently proven to impact the production of ROS, resulting in the clouding of the crystalline lens in newborns 3,4. Oxidative stress has since been correlated with several pathological or physiopathological conditions, including type 2 diabetes mellitus 3,4, senescence 5, 6, cardiovascular disease 7-11, cancer 12-14, pulmonary disease 15, 16, and hepatopathies 15, 16. However, to date, no study has investigated the link between oxidative stress and diseases of endodontic origin.…”

ROS and RNS Signaling in Skeletal Muscle: Critical Signals and Therapeutic Targets

“…ROS are formed as natural byproducts of oxygen metabolism and by enzymatic activity. In both cases, ROS production is highly localized and spatially restricted which makes it a efficient system for cell signaling processes such as glucose transport(Chambers, Moylan, Smith, et al, 2009), eicosanoid (Spiteller, 2010) and cytokine production (Sigala et al, 2011), and mitochondrial biogenesis (Austin, Klimcakova, & St-Pierre, 2011; Kang & Li Ji, 2012). However, during times of environmental stress (e.g., UV or hyperthermia), metabolic stress (e.g., hyperglycemia), or in disease states (e.g., muscular dystrophy, unloaded diaphragm during mechanical ventilation) ROS levels can increase dramatically resulting in aberrant signaling(D.…”

“…For example, oxidation, Snitrosylation (Foster, McMahon, & Stamler, 2003; Sun, Xin, Eu, Stamler, & Meissner, 2001), or S-glutathionylation of key cysteine in the RyR1 calcium release channel of skeletal muscle can significantly alter the mean open time and the permeability of the channel (Aracena-Parks et al, 2006; Hamilton & Reid, 2000; Hidalgo, et al, 2006). In addition to the RyR1, the sarcoendoplasmic reticulum calcium ATPase pump (i.e., SERCA pump) (Lehotsky, Kaplan, Murin, & Raeymaekers, 2002; Squier, 2001; Trebak, Ginnan, Singer, & Jourd'heuil, 2010) membrane lipids (Spiteller, 2010), or DNA (Ragu et al, 2007), CaMKinase (Franklin, Rodriguez–Mora, LaHair, & McCubrey, 2006; Pinto, de Sousa, & Sorenson, 2011) and contractile proteins(Ferreira, et al, 2012; Stasko, Hardin, Smith, Moylan, & Reid, 2013) have all been shown to be modified by ROS/RNS.…”