Regulation of S-Nitrosylation in Aging and Senescence
Abstract
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.
Keywords: GSNOR/ADH5; aging; cognitive dysfunction; nitric oxide signaling; senescence