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

Abstract

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 protein levels of Ngb in Spalax brain are 3-fold higher than in Rattus norvegicus under normoxia. Importantly, Spalax expresses Ngb in neurons and additionally in glia, whereas in hypoxia-sensitive rodents Ngb expression is limited to neurons. Hypoxia causes an approximately 2-fold downregulation of Ngb mRNA in brain of rat and mole rat. A parallel regulatory response was found for myoglobin (Mb) in Spalax and rat muscle, suggesting similar functions of Mb and Ngb. Cygb also revealed an augmented normoxic expression in Spalax vs. rat brain, but not in heart or liver, indicating distinct tissue-specific functions. Hypoxia induced Cygb transcription in heart and liver of both mammals, with the most prominent mRNA up-regulation (12-fold) in Spalax heart. Our data suggest that tissue globins contribute to the remarkable tolerance of Spalax toward environmental hypoxia. This is consistent with the proposed cytoprotective effect of Ngb and Cygb under pathological hypoxic/ischemic conditions in mammals.

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

“…A reactive role for neuroglobin is suggested by its upregulation by hypoxia in turtles, possibly as a mechanism to buffer reactive oxygen species during re-oxygenation (see also below). Neuroglobin levels were found to be higher in the blind mole-rat (Spalax) brain under normoxic conditions, but downregulated during hypoxia (Avivi et al, 2010).…”

“…One recently discovered potential antioxidant in the turtle is neuroglobin (Burmester et al, 2000), which has also been studied in other models of hypoxia tolerance (Avivi et al, 2010;Mitz et al, 2009;Roesner et al, 2008;Schneuer et al, 2012). Neuroglobin is strongly upregulated in both hypoxia and upon re-oxygenation in the turtle (Milton et al, 2006;Nayak et al, 2009), and decreasing neuroglobin expression with turtle-specific siRNA doubles ROS release upon re-oxygenation.…”

Cellular Basis for Learning Impairment in Fragile X Syndrome

“…One recently discovered potential antioxidant in the turtle is neuroglobin (Burmester et al, 2000), which has also been studied in other models of hypoxia tolerance (Avivi et al, 2010;Mitz et al, 2009;Roesner et al, 2008;Schneuer et al, 2012). Neuroglobin is strongly upregulated in both hypoxia and upon re-oxygenation in the turtle (Milton et al, 2006;Nayak et al, 2009), and decreasing neuroglobin expression with turtle-specific siRNA doubles ROS And finally, despite their remarkable tolerance to anoxia, histological examination of T. scripta brains that had not been exposed to anoxia in the lab showed some evidence of brain lesions, suggestive of prior damage probably occurring during long periods of anoxia during winter hibernation (S.L.M., unpublished observation).…”

“…A reactive role for neuroglobin is suggested by its upregulation by hypoxia in turtles, possibly as a mechanism to buffer reactive oxygen species during re-oxygenation (see also below). Neuroglobin levels were found to be higher in the blind mole-rat (Spalax) brain under normoxic conditions, but downregulated during hypoxia (Avivi et al, 2010).2. Low resting metabolism can be seen as a preparatory mechanism for energy conservation when hypoxic or ischemic episodes occur, at least in naked mole-rats and in hibernating arctic ground squirrels, although it does not explain intrinsic brain tolerance of hypoxia.…”

“…Recent work in the Milton laboratory has also shown that Hsp72 is involved in the reduction of ROS production (unpublished data). By affecting parts of the apoptotic pathway and possibly mitochondrial stability, then, the increases in Bcl-2, ERK1/2, AKT and certain HSPs are also likely to decrease oxidative stress during the recovery period, when ROS production might otherwise overwhelm even the high antioxidant levels of the turtle brain.One recently discovered potential antioxidant in the turtle is neuroglobin (Burmester et al, 2000), which has also been studied in other models of hypoxia tolerance (Avivi et al, 2010; Mitz et al, 2009;Roesner et al, 2008;Schneuer et al, 2012). Neuroglobin is strongly upregulated in both hypoxia and upon re-oxygenation in the turtle (Milton et al, 2006; Nayak et al, 2009), and decreasing neuroglobin expression with turtle-specific siRNA doubles ROS release upon re-oxygenation.…”