New insights into survival strategies to oxygen deprivation in anoxia‐tolerant vertebrates

Abstract

Hypoxic environments pose a severe challenge to vertebrates and even short periods of oxygen deprivation are often lethal as they constrain aerobic ATP production. However, a few ectotherm vertebrates are capable of surviving long-term hypoxia or even anoxia with little or no damage. Among these, freshwater turtles and crucian carp are the recognized champions of anoxia tolerance, capable of overwintering in complete oxygen deprivation for months at freezing temperatures by entering a stable hypometabolic state. While all steps of the oxygen cascade are adjusted in response to oxygen deprivation, this review draws from knowledge of freshwater turtles and crucian carp to highlight mechanisms regulating two of these steps, namely oxygen transport in the blood and oxygen utilization in mitochondria during three sequential phases: before anoxia, when hypoxia develops, during anoxia, and after anoxia at reoxygenation. In cold hypoxia, reduced red blood cell concentration of ATP plays a crucial role in increasing blood oxygen affinity and/or reducing oxygen unloading to tissues, to adjust aerobic metabolism to decrease ambient oxygen. In anoxia, metabolic rewiring of oxygen utilization keeps largely unaltered NADH/NAD + ratios and limits ADP degradation and succinate buildup. These critical adjustments make it possible to restart mitochondrial respiration and energy production with little generation of reactive oxygen species at reoxygenation when oxygen is again available. Inhibition of key metabolic enzymes seems to play crucial roles in these responses, in particular mitochondrial complex V, although identifying the nature of such inhibition(s) in vivo remains a challenge for future studies.

Metabolomic Profiling Reveals Differences in Hypoxia Response between Far Eastern and Siberian Frogs

“…However, under hypoxic conditions, other reactions are expected to occur. Specifically, α-ketoglutarate is expected to be converted to oxaloacetate through a transamination reaction that converts aspartate to glutamate [43]. This is supported by the fact that in Siberian frogs, all detected amino acids, except aspartate, significantly increased in concentration, while the latter was almost depleted.…”

“…The currently accepted view is that oxaloacetate is further converted to succinate via the reversal of the Krebs cycle [43][44][45]. Succinate is accumulated under hypoxia in organs of many mammals, including mice and humans [25,44,45], as well as in some hypoxiatolerant vertebrates, such as the crucian carp [23], and, to a lesser extent, in the diving turtle [24,25,46].…”

Does hypometabolism constrain innate immune defense?

“…The primary source of cellular ATP generation is aerobic cellular respiration, which is inherently dependent on oxygen availability. Hypoxia (i.e., decreased oxygen availability) thus impairs aerobic cellular respiration in the electron transport system 29 . Without a concomitant decrease in metabolic rate, the energy demands of an organism quickly outpace its energy supply, 30 which can result in cellular and eventually whole animal death.…”

“…Hypoxia (i.e., decreased oxygen availability) thus impairs aerobic cellular respiration in the electron transport system. 29 Without a concomitant decrease in metabolic rate, the energy demands of an organism quickly outpace its energy supply, 30 which can result in cellular and eventually whole animal death. Nonetheless, environmental hypoxia occurs in many ecosystems around the world and despite the challenges of living in hypoxia, many species thrive in these niches.…”

Carbon dioxide and MAPK signalling: towards therapy for inflammation

“…There are species of multicellular eukaryotes that tolerate periods of complete oxygen deprivation; e.g., the larvae of oriental fruit flies ( Bactrocera dorsalis ) can tolerate up to 24 h of anoxia without a significant reduction in survival [ 361 ]. In several species of fish adapted to life under completely oxygen-deprived conditions; for example, one of the clearest differences in crucian carp compared to aerobic species is the activity of pyruvate decarboxylase, which produces CO 2 independent of the Krebs cycle [ 362 , 363 ]. In addition, some turtles survive complete anoxic conditions, and upregulation of the prosurvival proteins ERK1/2 and suppression of p38 and JNK underlie neuronal survival [ 364 , 365 ].…”