Heterocephalus Research Articles

Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect.

Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO2 and lactic acid by a decreased extracellular pH. Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.

Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin.

Naked mole-rats (NMR) are subterranean rodents characterized by an unusual longevity coupled with an unexplained resistance to aging. In the present study, we performed extensive in situ analysis and single-cell RNA-sequencing comparing young and older animals. At variance with other species, NMR exhibited a striking stability of skin compartments and cell types, which remained stable over time without aging-associated changes. Remarkably, the number of stem cells was constant throughout aging. We found three classical cellular states defining a unique keratinocyte differentiation trajectory that were not altered after pseudo-temporal reconstruction. Epidermal gene expression did not change with aging either. Langerhans cell clusters were conserved, and only a higher basal stem cell expression of Igfbp3 was found in aged animals. In accordance, NMR skin healing closure was similar in young and older animals. Altogether, these results indicate that NMR skin is characterized by peculiar genetic and cellular features, different from those previously demonstrated for mice and humans. The remarkable stability of the aging NMR skin transcriptome likely reflects unaltered homeostasis and resilience.

Insights into the Evolution of Non‐shivering Thermogenesis from UCP1 of the Naked Mole Rat (Heterocephalus glaber)

Recognized as the primary location of non‐shivering thermogenesis (NST) in eutherian mammals, brown adipose tissue (BAT) functions to accelerate rewarming in hibernators and defend body temperature among newborns and small‐bodied species enduring cold stress. Uncoupling protein 1 (UCP1) is highly expressed in BAT and underlies the molecular mechanism of NST. UCP1 resides in the inner mitochondrial membrane where, upon functional induction by free fatty acids, it catalyzes mitochondrial proton leak, collapsing the proton gradient that stores oxidation energy. The ensuing futile cycling of protons increases substrate oxidation and thus heat production. Central questions remain regarding the exact mechanism by which UCP1 facilitates proton leak, stemming from the lack of a crystal structure of the protein. It is also unknown whether UCP1 function has been shaped by evolution to meet differing thermoregulatory demands of various lineages. We adopt a comparative approach, targeting species with extreme ecophysiological characteristics expected to culminate in drastic differences in thermoregulatory demands and thus UCP1 function, to provide insights into protein structure‐function relationships. For instance, the naked mole rat (NMR; Heterocephalus glaber) is well‐suited to survive in hypoxic burrows that exhibit high year‐round temperatures (30‐34°C). Hinting at a reduced NST capacity, NMRs also display poikilothermy, failing to maintain constant body temperatures when artificially cold challenged. Moreover, NMR UCP1 displays several unique amino acid substitutions, one of which, H145Q (histidine to glutamine), occurs at the well‐known “histidine pair motif”. This motif, typically comprised of histidines at positions 145 and 147, has been hypothesized to be a critical final proton acceptor/donor site shuttling protons into the mitochondrial matrix. The exact mutation that occurs in the NMR, H145Q, was previously shown to diminish hamster UCP1‐mediated proton conductance in proteoliposomes by 90%, calling the functional performance of NMR UCP1 into question. We functionally tested wildtype NMR UCP1 as well as histidine pair mutant combinations at positions 145 and 147, not in the highly artificial system of proteoliposomes, which may promote artefactual protein behaviour, but instead in the more native mammalian environment of HEK293 cells. Using plate‐based respirometry techniques, we demonstrate that wildtype NMR UCP1 uncouples, thus NMRs retain this mechanism of NST. While we hypothesized that reversion of the H145Q mutation would increase UCP1‐mediated proton leak, surprisingly both variants function similarly when activated with free fatty acids and inhibited with guanosine diphosphate (GDP). Likewise, mutation of the histidine at position 147, the other half of the “histidine pair motif”, does not drastically alter UCP1 function. Overall, these data suggest that the “histidine pair motif” may not be crucial for protein function, contrary to previous claims. Comparative functional assessments of UCP1 variants provide a deeper understanding of structure‐function relationships of this enigmatic protein and the evolution of mammalian NST in response to ecophysiological constraints.

Effects of tooth loss on anxiety‐like behaviors in Heterocephalus glaber

Tooth loss is an ailment affecting a large percentage of the population, particularly individuals of lower socioeconomic status and the elderly. Extensive tooth loss is known to result in anatomical changes in the face, including atrophy of masticatory muscles and decreases in mandibular and maxillary bone density, as well as volumetric changes within the brain. Human studies have reported strong correlations between tooth loss and levels of both anxiety and depression. However, little has been reported to date regarding the effect of dental health on emotional states, with only sparse information available from animal models regarding the psychiatric effects of tooth loss.Our study investigated the short‐term effects of tooth loss on anxiety‐like behaviors using Heterocephalus glaber, an animal with extensive sensory dedication to and behavioral reliance on its incisors. Adult naked mole‐rats underwent either tooth extraction or sham surgeries, followed by testing in both an open field maze and elevated plus maze in the weeks following. As there are no known studies to date that have utilized this animal model in behavioral tests of anxiety, our study provides critical information about the methodologies and modifications necessary to ascertain these important translational behavioral states so that future researchers can apply similar tests in other fields such as neurodegeneration, aging, and oncology.We hypothesized that tooth extraction will result in greater anxiety‐like behaviors, manifesting in various ways: greater defecation in the mazes, more time spent in the outer regions of the open field maze, and less time in the open arms of the elevated plus maze. The study demonstrated a trend towards tooth extraction increasing anxiety‐like behaviors in naked mole‐rats when investigated using the open field maze paradigm. There is evidence that, with an increase in sample sizes, this research will make evident the causal relationship of tooth loss and anxiety. Future research will investigate the long‐term behavioral changes associated with extensive tooth loss and the neurocircuitry associated with these behavioral alterations. Uncovering these details will provide potential therapeutic targets for negating the mental health difficulties associated with deficits in dental health.

Dampened inflammation drives cancer resistance in naked mole-rats.

Dampened inflammation drives cancer resistance in naked mole-rats.

SLC3A2 N‐glycosylation and alternate evolutionary trajectories for amino acid metabolism

Cancer and other proliferative diseases are driven by cooperative rewiring of growth signaling and metabolism, where posttranslational modifications to proteins play a critical role in maintaining the disease state. Most PTMs require metabolites as donor substrates, providing underappreciated link between metabolism and signaling. Protein N‐glycosylation and Golgi remodeling of N‐glycan on receptor kinases, T cell receptor, glucagon receptor, and glucose transporters provides feedback between signaling and metabolism. In turn, N‐glycosylation requires uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc), generated by the hexosamine biosynthesis pathway (HBP) from glucose, glutamine and acetyl‐CoA, where the flux of these substrates into UDP‐GlcNAc are in competition with glycolysis, glutaminolysis and fatty‐acid turnover. Thus, N‐glycan branching, a pathway of N‐acetylglucosaminyltransferases (MGAT1, 2, 4 and 5, avian 6) in the Golgi, is a sensor of central metabolism.In a search for additional glycoproteins that link metabolism, N‐glycosylation and signaling, we identified SLC3A2 (4F2hc, CD98),an adaptor to amino acid (AA) transporters SLC7A5‐11, ‐13 which stabilizes cell surface residency. The SLC3A2*SLC7A5 exchanger imports essential AA that stimulate mTOR signaling and anabolic metabolism, while SLC3A2*SLC7A11 supports glutathione synthesis and mitigation of oxidative stress. Analysis of SLC3A2 N‐glycans revealed stable site‐specific profiles of Golgi remodeling, with the exception of the conserved N365 where branching and poly‐N‐acetyllactosamine content were sensitive to the insertion of lost ancestral sites and to HBP. The N‐glycans are positioned to promote galectin‐mediated clustering with N‐glycosylated Na++/AA symporters and enhance diffusion‐limited flux between exchangers and AA /Na+ symporters. In a successful experiment of Nature, SLC3A2 has been deleted in Neoaves, a clade representing 95% of Ave species that are adapted for flapping flight, the most metabolically intense form of vertebrate locomotion. Neoaves have also acquired a unique N‐glycan branching specificity GnT‐VI (Mgat6, Q9DGD1), which may support an alternate clustering of N‐glycosylated transporters. KEAP1, and four SLC7A family exchangers are also absent, and two others have duplicated, consistent with a shift in metabolic imperatives of Neoaves. The fate of these genes in Primates, Neoaves and Naked mole rat highlights the tension between metabolic rates and oxidative stress that govern lifestyle and longevity.

Comparative Study of Protein Aggregation Propensity and Mutation Tolerance Between Naked Mole-Rat and Mouse.

The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies for healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes compared with mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat, and these are functionally involved in the inflammasome complex and nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared with the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.

Naked Mole-Rat Social Phenotypes Vary in Investigative and Aggressive Behavior in a Laboratory Partner Preference Paradigm

Here we employed the partner preference test (PPT) to examine how naked mole-rat non-breeding individuals of different behavioral phenotypes make social decisions. Naked mole-rats from six colonies were classified into three behavioral phenotypes (soldiers, dispersers, and workers) using a battery of behavioral tests. They then participated in a 3 h long PPT, where they could freely interact with a tethered familiar or tethered unfamiliar conspecific. By comparing the three behavioral phenotypes, we tested the hypothesis that the PPT can be used to interrogate social decision-making in this species, revealing individual differences in behavior that are consistent with discrete social phenotypes. We also tested whether a shorter, 10 min version of the paradigm is sufficient to capture group differences in behavior. Overall, soldiers had higher aggression scores toward unfamiliar conspecifics than both workers and dispersers at the 10 min and 3 h comparison times. At the 10 min comparison time, workers showed a stronger preference for the familiar animal’s chamber, as well as for investigating the familiar conspecific, compared to both dispersers and soldiers. At the 3 h time point, no phenotype differences were seen with chamber or investigation preference scores. Overall, all phenotypes spent more time in chambers with another animal vs. being alone. Use of the PPT in a comparative context has demonstrated that the test identifies species and group differences in affiliative and aggressive behavior toward familiar and unfamiliar animals, revealing individual differences in social decision-making and, importantly, capturing aspects of species-specific social organization seen in nature.

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

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. Thus, we aimed to reveal CNS related roles for PADs in hypoxia tolerance and identify whether circulating EV signatures may reveal a fingerprint for adaptive whole-body hypoxia responses in this species. We found that following in vivo acute hypoxia, NMR: (1) plasma-EVs were remodelled, (2) whole proteome EV cargo contained more protein hits (including citrullinated proteins) and a higher number of associated KEGG pathways relating to the total proteome of plasma-EVs Also, (3) brains had a trend for elevation in PAD1, PAD3 and PAD6 protein expression, while PAD2 and PAD4 were reduced, while (4) the brain citrullinome had a considerable increase in deiminated protein hits with hypoxia (1222 vs. 852 hits in normoxia). Our findings indicate that circulating EV signatures are modified and proteomic content is reduced in hypoxic conditions in naked mole-rats, including the circulating EV citrullinome, while the brain citrullinome is elevated and modulated in response to hypoxia. This was further reflected in elevation of some PADs in the brain tissue following acute hypoxia treatment. These findings indicate a possible selective role for PAD-isozymes in hypoxia response and tolerance.

The relationship between the naked mole-rat and hyaluronic acid, as mediated by its receptor CD44: A Mini-Review

The life expectancy of the naked mole-rat (Heterocephalus glaber) is longer than that of other rodents. In NMR cells, the hyaluronic acid concentration is at a higher level. The extracellular matrix’s primary constituent is hyaluronic acid, and CD44 and RHMM are the receptors for hyaluronic acid in the cells. Hyaluronan synthases (HAS); HAS1, HAS2, and HAS3 are located in the plasma membrane and produce hyaluronic acid. Moreover, there are six types of hyaluronic degradation enzymes (Hyal-1, Hyal-2, Hyal-3, Hyal-4, and PH-20). Hyaluronic acid is known to have anti-cancerous effects and acts as a double-edged sword promoting cell senescence and protecting against cellular aging at the same time. NMR’s lengthy lifespan may probably be due to the high molecular weight of hyaluronic acid. INK4 isoforms (P16ink4a/b and pALTINK4a/b) and p27kip1 conferring on NMR a 2-way (early and regular respectively) defense mechanism make NMR more resistant to cancer cells than, humans and mice with only regular contact inhibition (regular (p27kip1). This study, therefore, aims to examine the existing molecular interactions within the NMR-HA-CD44 axis and the ability to confer cancer resistance to mammalian cells through INK4 isoforms gene transfer using the CRISPR method. A lot of potential thus exists in studying these relationships and the prospects for answering the yet unknowns in this area.

Anecdotal observation of a sexual encounter between two male naked mole-rats

Abstract Same-sex sexual behaviours (SSBs) are widespread across the animal kingdom, yet little consensus exists regarding their potential adaptive functions or evolutionary history. To fully address questions such as why or how a trait has evolved, it is important to first understand its natural history. Here, we present evidence of SSBs in two male naked mole-rats for the first time. Due to extreme natal philopatry, most naked mole-rats never disperse, making encounters with potential mates valuable in fitness terms. However, in captive colonies of naked mole-rats, a rare disperser morph has been described. We speculate that such dispersing individuals may be indiscriminatory in their mating strategy, copulating with conspecifics regardless of sex, to counter the risk of missed reproductive opportunities. This behavioural strategy would contrast with the common characterisation of naked mole-rats, which describes them as fiercely xenophobic and hostile to unfamiliar individuals. Further, the observation of an indiscriminate mating strategy in a species with limited opportunities for dispersal provides interesting context for the study of the evolution of SSBs.

Immune competence and spleen size scale with colony status in the naked mole-rat.

Naked mole-rats (NM-R; Heterocephalus glaber) live in multi-generational colonies with a social hierarchy, and show low cancer incidence and long life-spans. Here we asked if an immune component might underlie such extreme physiology. The largest lymphoid organ is the spleen, which plays an essential role in responding to immunological insults and may participate in combating cancer and slowing ageing. We investigated the anatomy, molecular composition and function of the NM-R spleen using RNA-sequencing and histological analysis in healthy NM-Rs. Spleen size in healthy NM-Rs showed considerable inter-individual variability, with some animals displaying enlarged spleens. In all healthy NM-Rs, the spleen is a major site of adult haematopoiesis under normal physiological conditions. However, myeloid-to-lymphoid cell ratio is increased and splenic marginal zone showed markedly altered morphology when compared to other rodents. Healthy NM-Rs with enlarged spleens showed potentially better anti-microbial profiles and were much more likely to have a high rank within the colony. We propose that the anatomical plasticity of the spleen might be regulated by social interaction and gives immunological advantage to increase the lifespan of higher-ranked animals.

Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

Acute pH alterations do not impact cardiac mitochondrial respiration in naked mole-rats or mice

Energetically demanding conditions such as hypoxia and exercise favour anaerobic metabolism (glycolysis), which leads to acidification of the cellular milieu from ATP hydrolysis and accumulation of the anaerobic end-product, lactate. Cellular acidification may damage mitochondrial proteins and/or alter the H+ gradient across the mitochondrial inner membrane, which may in turn impact mitochondrial respiration and thus aerobic ATP production. Naked mole-rats are among the most hypoxia-tolerant mammals, and putatively experience intermittent environmental and systemic hypoxia while resting and exercising in their underground burrows. Previous studies in naked mole-rat brain, heart, and skeletal muscle mitochondria have demonstrated adaptations that favour improved efficiency in hypoxic conditions; however, the impact of cellular acidification on mitochondrial function has not been explored. We hypothesized that, relative to hypoxia-intolerant mice, naked mole-rat cardiac mitochondrial respiration is less sensitive to cellular pH changes. To test this, we used high-resolution respirometry to measure mitochondrial respiration by permeabilized cardiac muscle fibres from naked mole-rats and mice exposed in vitro to a pH range from 6.6 to 7.6. Surprisingly, we found that acute pH changes do not impact cardiac mitochondrial respiration or compromise mitochondrial integrity in either species. Our results suggest that acute alterations of cellular pH have minimal impact on cardiac mitochondrial respiration.

Stem-Cell Theory of Cancer: Implications for Antiaging and Anticancer Strategies.

Simple SummaryA stem-cell theory of cancer connects aging with cancer. It indicates that aging is a stemness process and cancer is a stem-cell disease. It implicates that a pertinent scientific strategy and proper research endeavor may provide us with realistic antiaging objectives and superior anticancer outcomes. In this perspective, we illustrate that a stem-cell origin of aging and cancer reiterates a fundamental oncological principle: although genetic makeup may be pivotal, cellular context is paramount. When the genome and epigenome that regulate aging and malignancy are also stemness genes and stem-like properties, they reaffirm the essential role stem-cell quality and quantity play in our lifespan and in the formation of cancer.A stem-cell theory of cancer predicates that not only does the cell affect the niche, the niche also affects the cell. It implicates that even though genetic makeup may be supreme, cellular context is key. When we attempt to solve the mystery of a long cancer-free life, perhaps we need to search no further than the genetics and epigenetics of the naked mole-rat. When we try to unlock the secrets in the longevity and quality of life, perhaps we need to look no further than the lifestyle and habits of the super centenarians. We speculate that people with Down’s syndrome and progeria age faster but have fewer cancers, because they are depleted of stem cells, and, as a consequence, have fewer opportunities for stem cell defects that could predispose them to the development of cancer. We contemplate whether these incredible experiments of nature may provide irrefutable evidence that cancer is a stem-cell disease—fewer aberrant stem cells, fewer cancers; no defective stem cells, no cancer. In this perspective, we investigate a stem-cell origin of aging and cancer. We elaborate an intriguing inverse relationship between longevity and malignancy in the naked mole-rat, in Down’s syndrome, and in progeria. We postulate that stem-cell pools and stemness factors may affect aging and dictate cancer. We propose that a healthy microbiome may protect and preserve stem cell reserves and provide meaningful antiaging effects and anticancer benefits.

Notes from underground: naked mole-rats and vocal dialects

Cooperation relies on shared communication systems, such as language. We can now add one of the planet’s most cooperative rodents, the naked mole-rat, to the short list of species that use vocal dialects to help identify group members. Using a combination of computer algorithms and behavioral studies, we recently identified some of the special features of naked mole-rat communication.

Stress in an underground empire.

The naked mole-rat (Heterocephalus glaber) and the Damaraland mole-rat (Fukomys damarensis) live in large colonies in underground tunnel systems in sub-Saharan Africa. Most members of the colonies are suppressed from reproduction and they are unlikely to reproduce during their lifetime. Only one female and a small number of males reproduce. This extreme cooperative social system has fascinated researchers since the naked mole-rat was first described as eusocial. Despite much research into the mechanisms of social suppression, the exact mechanisms are still unclear. Much evidence points towards high glucocorticoid concentrations caused by agonistic behaviour by the breeding female suppressing reproduction of non-breeders, but laboratory studies have not found any differences in glucocorticoids between breeders and non-breeders. There is, however, considerable evidence from field studies and other social mole-rats that social stress may indeed be an important factor of social suppression in social mole-rats and that those mechanisms are affected by the stability of the colony and environmental conditions. This review aims to provide a summary of the current knowledge of the relationship between environmental conditions, colony stability, glucocorticoids and reproductive suppression in social mole-rat species and suggests some avenues for future research.

Lactate inhibits naked mole-rat cardiac mitochondrial respiration.

In aerobic conditions, the proton-motive force drives oxidative phosphorylation (OXPHOS) and the conversion of ADP to ATP. In hypoxic environments, OXPHOS is impaired, resulting in energy shortfalls and the accumulation of protons and lactate. This results in cellular acidification, which may impact the activity and/or integrity of mitochondrial enzymes and in turn negatively impact mitochondrial respiration and thus aerobic ATP production. Naked mole-rats (NMRs) are among the most hypoxia-tolerant mammals and putatively experience intermittent hypoxia in their underground burrows. However, if and how NMR cardiac mitochondria are impacted by lactate accumulation in hypoxia is unknown. We predicted that lactate alters mitochondrial respiration in NMR cardiac muscle. To test this, we used high-resolution respirometry to measure mitochondrial respiration in permeabilized cardiac muscle fibres from NMRs exposed to 4h of in vivo normoxia (21% O2) or hypoxia (7% O2). We found that: (1) cardiac mitochondria cannot directly oxidize lactate, but surprisingly, (2) lactate inhibits mitochondrial respiration, and (3) decreases complex IV maximum respiratory capacity. Finally, (4) in vivo hypoxic exposure decreases the magnitude of lactate-mediated inhibition of mitochondrial respiration. Taken together, our results suggest that lactate may retard electron transport system function in NMR cardiac mitochondria, particularly in normoxia, and that NMR hearts may be primed for anaerobic metabolism.

Gene losses may contribute to subterranean adaptations in naked mole-rat and blind mole-rat

BackgroundNaked mole-rats (Heterocephalus glaber, NMRs) and blind mole-rats (Spalax galili, BMRs) are representative subterranean rodents that have evolved many extraordinary traits, including hypoxia tolerance, longevity, and cancer resistance. Although multiple candidate loci responsible for these traits have been uncovered by genomic studies, many of them are limited to functional changes to amino acid sequence and little is known about the contributions of other genetic events. To address this issue, we focused on gene losses (unitary pseudogenes) and systematically analyzed gene losses in NMRs and BMRs, aiming to elucidate the potential roles of pseudogenes in their adaptation to subterranean lifestyle.ResultsWe obtained the pseudogene repertoires in NMRs and BMRs, as well as their respective aboveground relatives, guinea pigs and rats, on a genome-wide scale. As a result, 167, 139, 341, and 112 pseudogenes were identified in NMRs, BMRs, guinea pigs, and rats, respectively. Functional enrichment analysis identified 4 shared and 2 species-specific enriched functional groups (EFGs) in subterranean lineages. Notably, the pseudogenes in these EFGs might be associated with either regressive (e.g., visual system) or adaptive (e.g., altered DNA damage response) traits. In addition, several pseudogenes including TNNI3K and PDE5A might be associated with specific cardiac features observed in subterranean lineages. Interestingly, we observed 20 convergent gene losses in NMRs and BMRs. Given that the functional investigations of these genes are generally scarce, we provided functional evidence that independent loss of TRIM17 in NMRs and BMRs might be beneficial for neuronal survival under hypoxia, supporting the positive role of eliminating TRIM17 function in hypoxia adaptation. Our results also suggested that pseudogenes, together with positively selected genes, reinforced subterranean adaptations cooperatively.ConclusionsOur study provides new insights into the molecular underpinnings of subterranean adaptations and highlights the importance of gene losses in mammalian evolution.

Adaptations to a hypoxic lifestyle in naked mole-rats.

Hypoxia is one of the strongest environmental drivers of cellular and physiological adaptation. Although most mammals are largely intolerant of hypoxia, some specialized species have evolved mitigative strategies to tolerate hypoxic niches. Among the most hypoxia-tolerant mammals are naked mole-rats (Heterocephalus glaber), a eusocial species of subterranean rodent native to eastern Africa. In hypoxia, naked mole-rats maintain consciousness and remain active despite a robust and rapid suppression of metabolic rate, which is mediated by numerous behavioural, physiological and cellular strategies. Conversely, hypoxia-intolerant mammals and most other hypoxia-tolerant mammals cannot achieve the same degree of metabolic savings while staying active in hypoxia and must also increase oxygen supply to tissues, and/or enter torpor. Intriguingly, recent studies suggest that naked mole-rats share many cellular strategies with non-mammalian vertebrate champions of anoxia tolerance, including the use of alternative metabolic end-products and potent pH buffering mechanisms to mitigate cellular acidification due to upregulation of anaerobic metabolic pathways, rapid mitochondrial remodelling to favour increased respiratory efficiency, and systemic shifts in energy prioritization to maintain brain function over that of other tissues. Herein, I discuss what is known regarding adaptations of naked mole-rats to a hypoxic lifestyle, and contrast strategies employed by this species to those of hypoxia-intolerant mammals, closely related African mole-rats, other well-studied hypoxia-tolerant mammals, and non-mammalian vertebrate champions of anoxia tolerance. I also discuss the neotenic theory of hypoxia tolerance - a leading theory that may explain the evolutionary origins of hypoxia tolerance in mammals - and highlight promising but underexplored avenues of hypoxia-related research in this fascinating model organism.