The brains of six African mole-rat species show divergent responses to hypoxia

Abstract

Mole-rats are champions of self-preservation, with increased longevity compared with other rodents their size, strong antioxidant capabilities and specialized defenses against endogenous oxidative stress. However, how the brains of these subterranean mammals handle acute in vivo hypoxia is poorly understood. This study is the first to examine the molecular response to low oxygen in six different species of hypoxia-tolerant mole-rats from sub-Saharan Africa. Protein carbonylation, a known marker of DNA damage (hydroxy-2′-deoxyguanosine), and antioxidant capacity did not change following hypoxia but HIF-1 protein levels increased significantly in the brains of two species. Nearly 30 miRNAs known to play roles in hypoxia tolerance were differentially regulated in a species-specific manner. The miRNAs exhibiting the strongest response to low oxygen stress inhibit apoptosis and regulate neuroinflammation, likely providing neuroprotection. A principal component analysis (PCA) using a subset of the molecular targets assessed herein revealed differences between control and hypoxic groups for two solitary species (Georychus capensis and Bathyergus suillus), which are ecologically adapted to a normoxic environment, suggesting a heightened sensitivity to hypoxia relative to species that may experience hypoxia more regularly in nature. By contrast, all molecular data were included in the PCA to detect a difference between control and hypoxic populations of eusocial Heterocephalus glaber, indicating they may require many lower-fold changes in signaling pathways to adapt to low oxygen settings. Finally, none of the Cryptomys hottentotus subspecies showed a statistical difference between control and hypoxic groups, presumably due to hypoxia tolerance derived from environmental pressures associated with a subterranean and social lifestyle.

The OxymiR response to oxygen limitation: a comparative microRNA perspective

“…MiR-31 and miR-153 antagonistically regulate the HIF pathway: miR-31 promotes its activation via the ablation of the HIF repressor, whereas miR-153 directly binds to the HIF-1α 3′-UTR and inhibits HIF-1α translation (Liu et al, 2010). This interaction demonstrates , anoxic freshwater crayfish (English et al, 2018) and hypoxic high-altitude Tibetan pigs (Zhang et al, 2015), and is down-regulated in hypoxic subterranean naked mole rats (Logan et al, 2020).…”

“…To explore the role of OxymiRs in naked mole rat neuroprotection, an international team of researchers examined a group of 27 hypoxia-associated miRNAs (Logan et al, 2020). Their results present miRNAs as modulators of neuroprotection in hypoxic mole rats; induction of hypoxia revealed that a subset of miRNAs are involved in inhibiting apoptosis and neuroinflammatory regulation (Logan et al, 2020) (Fig. 4).…”

“…4). Oxygen limitation is associated with the up-regulation of five miRNAs (miR-24-3p, -24-5p, -207, -27 and -592), whereas miR-210, -126 and -26 are down-regulated in response to hypoxia (Logan et al, 2020). As with the other hypoxic environments and animal models discussed above, Logan et al also reported that stress-responsive miRNAs such as miR-24 and miR-210 are differentially regulated in response to hypoxia, but the study also identified species-specific hypoxiainducible miRNAs.…”

“…The second multi-species study performed examined the miRNA responses in the brains of six African mole rat species with varying degrees of hypoxia tolerance, an analysis that included the abovementioned naked mole rat miRNAs (Logan et al, 2020). The greatest amount of differential miRNA expression was observed during hypoxia in the Cape mole rat (Georychus capensis) and the Cape dune mole rat (Bathyergus suillus), both of which are ecologically adapted to normoxic, not hypoxic, environments.…”

Adaptive Potential of the Heme Oxygenase/Carbon Monoxide Pathway During Hypoxia

“…For example, some diving mammals experience dramatic hypoxemia (Meir et al, 2009) and I/R events (Zapol et al, 1979) during their repeated long-duration breath-holds and do not develop injuries from this lifestyle. Species that have adapted to live at high altitude or under other hypoxic conditions (e.g., burrowing) also avoid pathologies associated with exposure to chronic hypoxia (Logan et al, 2020). These natural models offer unique insights into the adaptive mechanisms underlying tolerance to hypoxia and/or I/R injury.…”