Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria are key cellular organelles that play crucial roles in the energy production and regulation of cellular metabolism. Accumulating evidence suggests that mitochondrial activity can be modulated by nitric oxide (NO). As a key neurotransmitter in biologic systems, NO mediates the majority of its function through activation of the cyclic guanylyl cyclase (cGC) signaling pathway and S-nitrosylation of a variety of proteins involved in cellular functioning including those involved in mitochondrial biology. Moreover, excess NO or the formation of reactive NO species (RNS), e.g., peroxynitrite (ONOO-), impairs mitochondrial functioning and this, in conjunction with nuclear events, eventually affects neuronal cell metabolism and survival, contributing to the pathogenesis of several neurodegenerative diseases. In this review we highlight the possible mechanisms underlying the noxious effects of excess NO and RNS on mitochondrial function including (i) negative effects on electron transport chain (ETC); (ii) ONOO--mediated alteration in mitochondrial permeability transition; (iii) enhanced mitochondrial fragmentation and autophagy through S-nitrosylation of key proteins involved in this process such as dynamin-related protein 1 (DRP-1) and Parkin/PINK1 (protein phosphatase and tensin homolog-induced kinase 1) complex; (iv) alterations in the mitochondrial metabolic pathways including Krebs cycle, glycolysis, fatty acid metabolism, and urea cycle; and finally (v) mitochondrial ONOO--induced nuclear toxicity and subsequent release of apoptosis-inducing factor (AIF) from mitochondria, causing neuronal cell death. These proposed mechanisms highlight the multidimensional nature of NO and its signaling in the mitochondrial function. Understanding the mechanisms by which NO mediates mitochondrial (dys)function can provide new insights into the treatment of neurodegenerative diseases.
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PMID:Nitric Oxide and Mitochondrial Function in Neurological Diseases. 2946 5

Nitric oxide signals through several distinct mechanisms, including interaction with the heme group of guanylyl cyclase enzymes resulting in modulation of cGMP levels in the vascular endothelium. Alternatively, reactive nitrogen oxide species can bind cysteine residues in target proteins forming S-nitrosothiols. S-nitrosylation is recognized as an important post-translational modification of dozens of proteins, which plays a key role in cellular homeostasis, metabolism, and various disease states. By denitrosylating target proteins, S-nitrosoglutathione reductase (GSNOR/ADH5) plays a pivotal role in the regulation of protein S-nitrosylation. GSNOR expression is reduced in primary senescent cells that accumulate during aging in rodents and humans. Reduced GSNOR activity is accompanied by mitochondrial nitrosative stress, characterized by elevated S-nitrosylation of Drp1 and Parkin with the downstream effect of impaired mitophagy. The mechanism involves epigenetic downregulation of GSNOR by the ten-eleven translocation 1 protein. Conflicting recent reports show that GSNOR levels change with age in mice and humans. One report found that GSNOR levels decreased in peripheral blood mononuclear cell and brains of young to middle-aged mice. However, another report more convincingly showed that there was a significant increase in the hippocampal expression of GSNOR in both old humans and mice. Increased GSNOR in old mice resulted in loss of synaptic plasticity and reduced long-term potentiation memory, in part, by reducing calmodulin kinase IIa activation, which is known to increase the number of AMPA glutamate receptors near synapses. GSNOR levels may be a key biochemical hallmark of aging, but subject to the Goldilocks principle such that its levels need to be maintained in a narrow range according to context, making it a problematic therapeutic target in aging as opposing changes in expression or activity would be needed to stimulate mitophagy in senescence and synaptic plasticity in aging brains.
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PMID:Regulation of S-Nitrosylation in Aging and Senescence. 3129 16