What can naked mole-rats teach us about ameliorating hypoxia-related human diseases?

Ameliorating the deleterious impact of systemic or tissue-level hypoxia or ischemia is key to preventing or treating many human diseases and pathologies. Usefully, environmental hypoxia is also a common challenge in many natural habitats; animals that are native to such hypoxic niches often exhibit strategies that enable them to thrive with limited O availability. Studying how such species have evolved to tolerate systemic hypoxia offers a promising avenue of discovery for novel strategies to mitigate the deleterious effects of hypoxia in human diseases and pathologies.

Apocynin reduces dihydroethidium fluorescence in naked mole-rat cortex independently of NADPH oxidase.

Pharmacological agents that modulate cellular targets offer a powerful approach to interrogate the role of a given component in cellular signalling cascades. However, such drugs are often nonspecific and/or have unexpected off-target effects. One cellular target of interest is the NADPH oxidase (NOX) enzyme family, which consume oxygen and produce reactive oxygen species.

Small RNA sequencing in hypoxic naked mole-rat hearts suggests microRNA regulation of RNA- and translation-related processes.

The naked mole-rat (Heterocephalus glaber) regularly endures intermittent periods of hypoxia in its burrows, surviving in part due to metabolic rate depression (MRD)-a strategy of conserving cellular resources by downregulating nonessential gene expression and reorganizing cellular processes. miRNA are short, noncoding RNAs already implicated for their roles in numerous models of extreme environmental stress; given their rapid, reversible nature, they are ideal for implementing MRD. We performed small RNA sequencing on cardiac tissue from normoxic versus 24 h hypoxic naked mole-rats, and used bioinformatics to predict 18 miRNAs which may be differentially regulated during hypoxia.

Naked mole-rats resist the accumulation of hypoxia-induced oxidative damage.

Naked mole-rats are among the few mammals with the ability to endure severe hypoxia. These unique rodents use metabolic rate depression along with various molecular mechanisms to successfully overcome the challenges of oxygen-limitation, which they experience in their underground borrows. While studies have reported that naked mole-rats exhibit inherently higher levels of oxidative damage across their lifespan as compared to mice, it has yet to be determined whether naked mole-rats are vulnerable to oxidative damage during periods of low oxygen exposure.

What to do with low O: Redox adaptations in vertebrates native to hypoxic environments.

Reactive oxygen species (ROS) are important cellular signalling molecules but sudden changes in redox balance can be deleterious to cells and lethal to the whole organism. ROS production is inherently linked to environmental oxygen availability and many species live in variable oxygen environments that can range in both severity and duration of hypoxic exposure. Given the importance of redox homeostasis to cell and animal viability, it is not surprising that early studies in species adapted to various hypoxic niches have revealed diverse strategies to limit or mitigate deleterious ROS changes.

Acute Hypoxia Alters Extracellular Vesicle Signatures and the Brain Citrullinome of Naked Mole-Rats ().

Peptidylarginine deiminases (PADs) and extracellular vesicles (EVs) may be indicative biomarkers of physiological and pathological status and adaptive responses, including to diseases and disorders of the central nervous system (CNS) and related to hypoxia. While these markers have been studied in hypoxia-intolerant mammals, in vivo investigations in hypoxia-tolerant species are lacking. Naked mole-rats (NMR) are among the most hypoxia-tolerant mammals and are thus a good model organism for understanding natural and beneficial adaptations to hypoxia.

Naked Mole-Rat Cortex Maintains Reactive Oxygen Species Homeostasis During Hypoxia or Ischemia and Reperfusion.

Neuronal injury during acute hypoxia, ischemia, and following reperfusion are partially attributable to oxidative damage caused by deleterious fluctuations of reactive oxygen species (ROS). In particular, mitochondrial superoxide (O•-) production is believed to upsurge during lowoxygen conditions and also following reperfusion, before being dismutated to HO and released into the cell. However, disruptions of redox homeostasis may be beneficially attenuated in the brain of hypoxia-tolerant species, such as the naked mole-rat (NMR, Heterocephalus glaber).

MicroRNA-mediated inhibition of AMPK coordinates tissue-specific downregulation of skeletal muscle metabolism in hypoxic naked mole-rats.

Naked mole-rats reduce their metabolic requirements to tolerate severe hypoxia. However, the regulatory mechanisms that underpin this metabolic suppression have yet to be elucidated. 5'-AMP-activated protein kinase (AMPK) is the cellular 'master' energy effector and we hypothesized that alterations in the AMPK pathway contribute to metabolic reorganization in hypoxic naked mole-rat skeletal muscle.

Nitric oxide homeostasis is maintained during acute in vitro hypoxia and following reoxygenation in naked mole-rat but not mouse cortical neurons.

Reactive nitrogen species (RNS), including nitric oxide (NO), are important cellular messengers when tightly regulated, but unregulated production of RNS during hypoxia or ischemia and reoxygenation is deleterious to hypoxia-intolerant brain. Therefore, maintaining NO homeostasis during hypoxia/ischemia and reoxygenation may be a hallmark of hypoxia-tolerant brain. Unlike most mammals, naked mole-rats (NMRs; Heterocephalus glaber) are tolerant of repeated bouts of hypoxia in vivo.