Neuroglobin and cytoglobin in search of their role in the vertebrate globin family

Neuroglobin and cytoglobin are two recent additions to the family of heme-containing respiratory proteins of man and other vertebrates. Here, we review the present state of knowledge of the structures, ligand binding kinetics, evolution and expression patterns of these two proteins. These data provide a first glimpse into the possible physiological roles of these globins in the animal's metabolism. Both, neuroglobin and cytoglobin are structurally similar to myoglobin, although they contain distinct cavities that may be instrumental in ligand binding. Kinetic and structural studies show that neuroglobin and cytoglobin belong to the class of hexa-coordinated globins with a biphasic ligand-bi…

Molecular evolution of antioxidant and hypoxia response in long-lived, cancer-resistant blind mole rats: The Nrf2-Keap1 pathway.

The Nrf2-Keap1 pathway is crucial for the cellular antioxidant and hypoxia response in vertebrates. Deciphering its modifications in hypoxia-adapted animals will help understand its functionality under environmental stress and possibly allow for knowledge transfer into biomedical research. The blind mole rat Spalax, a long-lived cancer-resistant rodent, lives in burrows underground and is adapted to severely hypoxic conditions. Here we have conducted a bioinformatical survey of Spalax core genes from the Nrf2-Keap1 pathway on the coding sequence level in comparison to other hypoxia-tolerant and -sensitive rodents. We find strong sequence conservation across all genes, illustrating the pathw…

Corrigendum to “Living with stress: Regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax” [Gene 500 (2012) 199–206]

Cytoglobin is a respiratory protein in connective tissue and neurons, which is up-regulated by hypoxia.

Cytoglobin is a recently discovered vertebrate globin distantly related to myoglobin, and its function is unknown. Here we present the first detailed analysis of the distribution and expression of cytoglobin. Northern and Western blotting experiments show the presence of cytoglobin mRNA and protein in a broad range of tissues. Quantitative PCR demonstrates an up-regulation of cytoglobin mRNA levels in rat heart and liver under hypoxic conditions (22 and 44 h of 9% oxygen). Immunofluorescence studies with three antibodies directed against different epitopes of the protein consistently show cytoglobin in connective tissue fibroblasts as well as in hepatic stellate cells. Cytoglobin is also pr…

Neuroglobin, cytoglobin, and myoglobin contribute to hypoxia adaptation of the subterranean mole rat Spalax.

The subterranean mole rat Spalax is an excellent model for studying adaptation of a mammal toward chronic environmental hypoxia. Neuroglobin (Ngb) and cytoglobin (Cygb) are O 2 -binding respiratory proteins and thus candidates for being involved in molecular hypoxia adaptations of Spalax . Ngb is expressed primarily in vertebrate nerves, whereas Cygb is found in extracellular matrix-producing cells and in some neurons. The physiological functions of both proteins are not fully understood but discussed with regard to O 2 supply, the detoxification of reactive oxygen or nitrogen species, and apoptosis protection. Spalax Ngb and Cygb coding sequences are strongly conserved. However, mRNA and …

Living with stress: regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax.

Lack of oxygen is life threatening for most mammals. It is therefore of biomedical interest to investigate the adaptive mechanisms which enable mammalian species to tolerate extremely hypoxic conditions. The subterranean mole rat Spalax survives substantially longer periods of hypoxia than the laboratory rat. We hypothesized that genes of the antioxidant defense, detoxifying harmful reactive oxygen species generated during hypoxia and hyperoxia, are involved in Spalax underground adaptation. Using quantitative RT-PCR, we analyzed the mRNA expression levels of seven antioxidant defense genes (catalase, glutathione peroxidase 1, glutathione-S-transferase Pi1, heme oxygenase 1, superoxide dism…

Genomic Organization and Molecular Evolution of the Genes for Neuroglobin and Cytoglobin in the Hypoxiatolerant Israeli Mole Rat, Spalax Carmeli

The genes for the two respiratory proteins neuroglobin (Ngb) and cytoglobin (Cygb) in the subterranean Israeli mole rat Spalax carmeli have been sequenced and compared to other mammals including human. Coding regions of both Spalax genes are highly conserved on the nucleotide and amino acid level. The ratios of non-synonymous to synonymous nucleotide substitutions suggest strong purifying selection acting on Ngb and Cygb in all mammals. Thus, there appears to be no special sequence level adaptation in the two respiratory proteins within the hypoxia-tolerant mole rat. On the genomic level, Spalax Ngb and Cygb gene regions revealed the conserved 4-exon-3-intron structure and conserved CpG-ric…

Genome-wide adaptive complexes to underground stresses in blind mole rats Spalax

The blind mole rat (BMR), Spalax galili, is an excellent model for studying mammalian adaptation to life underground and medical applications. The BMR spends its entire life underground, protecting itself from predators and climatic fluctuations while challenging it with multiple stressors such as darkness, hypoxia, hypercapnia, energetics and high pathonecity. Here we sequence and analyse the BMR genome and transcriptome, highlighting the possible genomic adaptive responses to the underground stressors. Our results show high rates of RNA/DNA editing, reduced chromosome rearrangements, an over-representation of short interspersed elements (SINEs) probably linked to hypoxia tolerance, degene…