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Reactive Dicarbonyls and Mitochondrial Dysfunction Although mitochondrial dysfunction has been suggested to be one of the main pathogenic mechanisms in diabetic neuropathy, little is known about the nature and extent of mitochondrial damage resulting from chronic hyperglycemia. Mitochondria function in calcium homeostasis and a wide range of biochemical reactions, including fatty ret pathway oxidation, nutrient production in the citric acid cycle, oxidative phosphorylation, and ATP production. Mitochondria are responsible for producing energy that cells harness for all cellular processes such as protein production, cellular transport, and cell growth and maintenance. Oxidation of NADH and FADH2 from glycolysis, beta oxidation, and citric acid cycle releases electrons that are passed through a coordinated series of enzyme complexes located in the mitochondrial inner membrane and are finally transferred to oxygen. Complexes from the oxidative phosphorylation pathway use the redox energy released during electron transfer to pump protons from the mitochondrial matrix into the intermembrane space, which creates an electrochemical gradient across the inner mitochondrial membrane. ATP Synthase or Complex V uses the electrochemical gradient to produce ATP. This process is particularly important for neurons given their relatively high reliance on energy production as a result of their increased metabolic demands. Consequently, mitochondrial damage and dysfunction have been linked to common neurological disorders including diabetic neuropathy.86, 87, 88 One mechanism by which elevated intracellular reactive dicarbonyls clearly alters mitochondrial function is through glycation of mitochondrial proteins. Multiple studies have shown that reactive dicarbonyls form AGEs on mitochondrial oxidative phosphorylation proteins and produce changes in mitochondrial respiration, activity of oxidative phosphorylation proteins, and leakage of electrons from these complexes in tissues that develop secondary complications of diabetes mellitus.73, 89, 90, 91 However, some dispute remains whether mitochondrial dysfunction results in the production of reactive oxygen species and oxidative stress in sensory neurons. A large body of evidence supporting the idea that reactive dicarbonyl damage to mitochondria results in oxidative stress comes from studies in tissues other than the peripheral nervous system.73, 89, 91, 92, 93 Although the axons of DRG neurons from diabetic rats exhibited increased ROS and oxidative stress, impaired respiratory function and reduced expression of certain mitochondrial oxidative phosphorylation proteins resulted in reduced production of superoxide.95, 96
The Glyoxalase System and Protection From Ages The glyoxalase system, which is composed of the enzymes glyoxalase I (GLO1) and glyoxalase II (GLO2) is one mechanism that protects against AGE production. The glyoxalase system is responsible for detoxifying reactive dicarbonyls prior to the formation of an AGE (Fig 1, Fig 2) and was discovered independently by Dakin, Dudley, and Neuberg in 1913. At that time, its function of catalyzing the conversion of methylglyoxal to lactate was also described.35, 44 Future studies revealed that reactive dicarbonyls, like methylglyoxal, react with reduced glutathione forming a hemithioacetal97, 98 (Fig 2). GLO1 converts the hemithioacetal to S-2-hydroxyacetylglutathione. GLO2 then catalyzes this intermediate to the corresponding α-hydroxyacid and releases reduced glutathione. GLO1 is considered the key enzyme in anti-glycation defense because it is the rate-limiting step in the glyoxalase pathway and prevents the accumulation of reactive dicarbonyls.100, 101 GLO1 is highly conserved with the enzyme being described in humans, mice, yeast, plants, insects, protozoa, fungi, and many bacterial strains. As a result of its critical function, GLO1 has been reported to be ubiquitously expressed in the cytosol of all cells.44, 99, 102, 103 However, we have shown Glo1 is primarily expressed at high abundance in small, unmyelinated peptidergic neurons, a subset of DRG neurons that are responsible for pain transmission in the peripheral nervous system (Fig 3). The loss of peptidergic epidermal innervation has been shown to be correlated with the development of thermal and mechanical insensitivity.