Selective Vulnerability of Synaptic Signaling and Metabolism to Nitrosative Stress

Abstract

Significance: Nitric oxide (NO) plays diverse physiological roles in the central nervous system, where it modulates neuronal communication, regulates blood flow, and contributes to the innate immune responses. In a number of brain pathologies, the excessive production of NO also leads to the formation of reactive and toxic intermediates generically termed reactive nitrogen species (RNS). RNS cause irreversible or poorly reversible damage to brain cells. Recent Advances: Recent work in the field focused on the ability of NO and RNS to yield protein modifications, including the S-nitrosation of cysteine residues, which, in many instances, impact cellular functions and viability. Critical Issues: The vast majority of neuropathological studies focus on the loss of cell viability, but nitrosative stress may also strongly impair the functions of neuronal processes: axonal projections and dendritic trees. The functional integrity of axons and dendrites critically depends on local metabolism and effective delivery of metabolic enzymes and organelles. Here, we summarize the existing literature describing the effects of nitrosative stress on the major pathways of energetic metabolism: glycolysis, tricarboxylic acid cycle, and mitochondrial respiration, with the emphasis on modifications of protein thiols. Future Directions: We propose that axons and dendrites are highly vulnerable to nitrosative stress because of their low glycolytic capacity and high dependence on timely delivery of metabolic enzymes and organelles from the cell body. Thus, supplementation with the end products of glycolysis, pyruvate or lactate, may help preserve metabolism in distal neuronal processes and protect or restore synaptic function in the ailing brain. Antioxid. Redox Signal. 17, 992-1012.

Cell Volume Control in Healthy Brain and Neuropathologies

“…Nevertheless, the penumbral tissue is electrically silent as a result of presynaptic failure (Bolay & Dalkara, 1998; Neumann-Haefelin & Witte, 2000; Bolay et al, 2002). This is explained by the difficulties in sustaining metabolism in remote axonal processes and oxidative/nitrosative modification in presynaptic processes [reviewed in (Mongin, Dohare, & Jourd’heuil, 2012)]. Astrocytic swelling in the penumbra likely involves numerous mechanisms, including but not limited to osmolyte fluxes via the Na + -dependent transporters (GLT-1, GLAST, and others).…”

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

“…Accumulating evidence suggests that impairment in these mitochondrial processes in neurons leads to synaptic dysfunction and eventually neuronal cell death, and is implicated in the pathophysiology of neurodegenerative diseases [34–36]. For example, the activities of aconitase, isocitrate dehydrogenase, and αKGDH in the TCA cycle are low in AD [37], and defects in mitochondrial function due to environmental insult or mutation in mitochondrial DNA are associated with PD [38–40].…”

Nitric oxide and energy metabolism in mammals

“…Consistent with reduced oxygen consumption, micromolar concentrations of NO inhibit the oxidation of fatty acids and glucose by up to 90% in all cell types . In contrast, physiological levels of NO stimulate glucose uptake and oxidation by 25–40%, as well as fatty acid uptake and oxidation by 30–40% in insulin‐sensitive tissues (muscle, heart, liver, and adipose tissue), while inhibiting the synthesis of glucose, glycogen and fat by 25–40% in target tissues ( e.g ., liver and adipose) and enhancing lipolysis by 25–30% in white adipocytes .…”