Skip to main content

African Naked Mole-Rats Demonstrate Extreme Tolerance to Hypoxia and Hypercapnia

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 1319)

Abstract

Naked mole-rats are extremely tolerant to low concentrations of oxygen (hypoxia) and high concentrations of carbon dioxide (hypercapnia), which is consistent with the environment that they inhabit. Naked mole-rats combine subterranean living with living in very densely populated colonies where oxygen becomes depleted and carbon dioxide accumulates. In the laboratory, naked mole-rats fully recover from 5 h exposure to 5% O2 and 5 h exposure to 80% CO2, whereas both conditions are rapidly lethal to similarly sized laboratory mice. During anoxia (0% O2) naked mole-rats enter a suspended animation-like state and switch from aerobic metabolism of glucose to anaerobic metabolism of fructose. Additional fascinating characteristics include that naked mole-rats show intrinsic brain tolerance to anoxia; a complete lack of hypoxia-induced and CO2-induced pulmonary edema; and reduced aversion to high concentrations of CO2 and acidic fumes. Here we outline a constellation of physiological and molecular adaptations that correlate with the naked mole-rat’s hypoxic/hypercapnic tolerance and which offer potential targets for ameliorating pathological conditions in humans, such as the damage caused during cerebral ischemia.

figure a

Photo Credit: Thomas Park

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-030-65943-1_9
  • Chapter length: 15 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   129.00
Price excludes VAT (USA)
  • ISBN: 978-3-030-65943-1
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   169.99
Price excludes VAT (USA)
Fig. 9.1
Fig. 9.2
Fig. 9.3
Fig. 9.4
Fig. 9.5
Fig. 9.6
Fig. 9.7
Fig. 9.8
Fig. 9.9
Fig. 9.10
Fig. 9.11
Fig. 9.12
Fig. 9.13

References

  • Bärtsch P, Mairbäurl H, Maggiorini M, Swenson ER (2005) Physiological aspects of high-altitude pulmonary edema. J Appl Physiol 98:1101–1110

    CrossRef  Google Scholar 

  • Bennett NC, Faulkes CG (2000) African Mole-Rats: Ecology and Eusociality. Cambridge University Press, Cambridge

    Google Scholar 

  • Bickler PE (2004) Clinical perspectives: neuroprotection lessons from hypoxia-tolerant organisms. J Exp Biol 207:3243–3249

    CAS  CrossRef  Google Scholar 

  • Bickler PE, Fahlman CS, Taylor DM (2003) Oxygen sensitivity of NMDA receptors: relationship to NR2 subunit composition and hypoxia tolerance of neonatal neurons. Neuroscience 118:25–35

    CAS  CrossRef  Google Scholar 

  • Blackstone E, Roth MB (2007) Suspended animation-like state protects mice from lethal hypoxia. Shock 27:370–372

    CAS  CrossRef  Google Scholar 

  • Blackstone E, Morrison M, Roth MB (2005) H2S induces a suspended animation-like state in mice. Science 308(5721):518

    CAS  CrossRef  Google Scholar 

  • Buffenstein R, Craft W (2021) The idiosyncratic physiological traits of the naked mole-rat; a resilient animal model of aging, longevity, and healthspan. In: Buffenstein R, Park TJ, Holmes MM (eds) The Extraordinary Biology of the Naked Mole-Rat. Springer, New York, pp 221–254

    Google Scholar 

  • Buffenstein R, Yahav S (1991) Is the naked mole-rat Heterocephalus glaber an endothermic yet poikilothermic mammal? J Therm Biol 16:227–232

    Google Scholar 

  • Deshpande JK, Siesjo BK, Wieloch T (1987) Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia. J Cereb Blood Flow Metab 7:89–95

    CAS  CrossRef  Google Scholar 

  • Eigenbrod O, Debus KY, Reznick J, Bennett NC, Sánchez-Carranza O, Omerbašić D, Hart DW, Barker AJ, Zhong W, Lutermann H, Katandukila JV, Mgode G, Park TJ, Lewin GR (2019) Rapid molecular evolution of pain insensitivity in multiple African rodents. Science 364(6443):852–859

    CAS  CrossRef  Google Scholar 

  • Fang X, Seim I, Huang Z, Gerashchenko MV, Xiong Z, Turanov AA, Zhu Y, Lobanov AV, Fan D, Yim SH, Yao X, Ma S, Yang L, Lee SG, Kim EB, Bronson RT, Šumbera R, Buffenstein R, Zhou X, Krogh A, Park TJ, Zhang G, Wang J, Gladyshev VN (2014) Adaptations to a subterranean environment and longevity revealed by the analysis of mole rat genomes. Cell Rep 8:1354–1364

    CAS  CrossRef  Google Scholar 

  • Farhat E, Devereaux MEM, Pamenter ME, Weber J-M (2020) Naked mole-rats suppress energy metabolism and modulate membrane cholesterol in chronic hypoxia. Am J Physiol Regul Integr Comp Physiol 319:R148–R155

    CAS  CrossRef  Google Scholar 

  • Germonpré PR, Joos GF, Pauwels RA (1995) Characterization of the neurogenic plasma extravasation in the airways. Arch Int Pharmacodyn Ther 329:185–203

    PubMed  Google Scholar 

  • Gourine AV (2005) On the peripheral and central chemoreception and control of breathing: an emerging role of ATP. J Physiol 568:715–724

    CAS  CrossRef  Google Scholar 

  • Guais A, Brand G, Jacquot L, Karrer M, Dukan S, Grévillot G, Molina TJ, Bonte J, Regnier M, Schwartz L (2011) Toxicity of carbon dioxide: a review. Chem Res Toxicol 24:2061–2070

    CAS  CrossRef  Google Scholar 

  • Hacker L, Brunker J, Smith ESJ, Quiros-Gonzalez I, Bohndiek SE (2020) Photoacoustics resolves species-specific differences in hemoglobin concentration and oxygenation. J Biomed Opt 25:095002

    Google Scholar 

  • Husson Z, Smith ESJ (2018) Naked mole-rat cortical neurons are resistant to acid-induced cell death. Mol Brain 11:26

    Google Scholar 

  • Johansen K, Lykkeboe G, Weber RE, Maloiy GM (1976) Blood respiratory properties in the naked mole rat Heterocephalus glaber, a mammal of low body temperature. Respir Physiol 28(3):303–314

    Google Scholar 

  • Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P, Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ, Zhang G, Wang J, Gladyshev VN (2011) Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479(7372):223–227

    CAS  CrossRef  Google Scholar 

  • King TE, Barr GA (2003) Functional development of neurokinin peptides substance P and neurokinin a in nociception. Neuroreport 14:1603–1607

    CAS  CrossRef  Google Scholar 

  • Kirschbaum TH, DeHaven JC (1968) Maternal and fetal blood constituents. In: Assali NS (ed) The Fetus and Neonate. Academic, New York, pp 143–187

    Google Scholar 

  • Larson J, Park TJ (2009) Extreme hypoxia tolerance of naked mole-rat brain. NeuroReport 20:1634–1637

    CrossRef  Google Scholar 

  • Larson J, Drew KL, Folkow LP, Milton SL, Park TJ (2014) No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. J Exp Biol 217:1024–1039

    CAS  CrossRef  Google Scholar 

  • Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH (1997) Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 51:23–32

    Google Scholar 

  • LaVinka PC, Park TJ (2012) Blunted behavioral and c Fos responses to acidic fumes in the African naked mole-rat. PLoS One 7(9):e45060

    CAS  CrossRef  Google Scholar 

  • Lee LY, Pisarri TE (2001) Afferent properties and reflex functions of bronchopulmonary C-fibers. Respir Physiol 125:47–65

    CAS  CrossRef  Google Scholar 

  • Lee KS, Frank S, Vaderklish P, Arai A, Lynch G (1991) Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci U S A 88:7233–7237

    CAS  CrossRef  Google Scholar 

  • Lewin GR, Smith ESJ, Reznick J, Debus K, Barker A, Park TJ (2021) The somatosensory world of the African naked mole-rat. In: Buffenstein R, Park TJ, Holmes MM (eds) The Extraordinary Biology of the Naked Mole-Rat. Springer, New York, pp 197–220

    Google Scholar 

  • Orr ME, Garbarino VR, Salinas A, Buffenstein R (2016) Extended postnatal brain development in the longest-lived rodent: prolonged maintenance of Neotenous traits in the naked mole-rat brain. Front Neurosci 10:504

    CrossRef  Google Scholar 

  • Pamenter ME, Dzal YA, Thompson WA, Milsom WK (2018) Do naked mole rats accumulate a metabolic acidosis or an oxygen debt in severe hypoxia? J Exp Biol 222: jeb191197

    Google Scholar 

  • Park TJ, Comer C, Carol A, Lu Y, Hong HS, Rice FL (2003) Somatosensory organization and behavior in naked mole-rats: II. Peripheral structures, innervation, and selective lack of neuropeptides associated with thermoregulation and pain. J Comp Neurol 465:104–120

    CrossRef  Google Scholar 

  • Park TJ, Lu Y, Jüttner R, Smith ES, Hu J, Brand A, Wetzel C, Milenkovic N, Erdmann B, Heppenstall PA, Laurito CE, Wilson SP, Lewin GR (2008) Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber). PLoS Biol 6(1):e13

    Google Scholar 

  • Park TJ, Reznick J, Peterson BL, Blass G, Omerbašić D, Bennett NC, Kuich PHJL, Zasada C, Browe BM, Hamann W, Applegate DT, Radke MH, Kosten T, Lutermann H, Gavaghan V, Eigenbrod O, Bégay V, Amoroso VG, Govind V, Minshall RD, Smith ESJ, Larson J, Gotthardt M, Kempa S, Lewin GR (2017) Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356(6335):307–311

    CAS  CrossRef  Google Scholar 

  • Penz OK, Fuzik J, Kurek AB, Romanov R, Larson J, Park TJ, Harkany T, Keimpema E (2015) Protracted brain development in a rodent model of extreme longevity. Sci Rep 5:11592

    CAS  CrossRef  Google Scholar 

  • Peterson BL, Larson J, Buffenstein R, Park TJ, Fall CP (2012a) Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus. PLoS One 7:e31568

    Google Scholar 

  • Peterson BL, Park TJ, Larson J (2012b) Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals. Neurosci Lett 506:342–345

    CAS  CrossRef  Google Scholar 

  • Pritchett K, Corrow D, Stockwell J, Smith A (2005) Euthanasia of neonatal mice with carbon dioxide. Comp Med 55:275–281

    CAS  PubMed  Google Scholar 

  • Reznick J, Park TJ, Lewin GR (2021) A sweet story of metabolic innovation in the naked mole-rat. In: Buffenstein R, Park TJ, Holmes MM (eds) The Extraordinary Biology of the Naked Mole-Rat. Springer, New York, pp 271–286

    Google Scholar 

  • Russell NJ, Raybould HE, Trenchard D (1984) Role of vagal C-fiber afferents in respiratory response to hypercapnia. J Appl Physiol 56:1550–1558

    CAS  CrossRef  Google Scholar 

  • Schuhmacher LN, Smith ES (2016) Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat. Mol Brain 9:97

    CrossRef  Google Scholar 

  • Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22:657–682

    CAS  CrossRef  Google Scholar 

  • Smith ESJ, Omerbašić D, Lechner SG, Anirudhan G, Lapatsina L, Lewin GR (2011) The molecular basis of acid insensitivity in the African naked mole-rat. Science 334(6062):1557–1560

    Google Scholar 

  • Smith ESJ, Purfürst B, Grigoryan T, Park TJ, Bennett NC, Lewin GR (2012) A specific paucity of unmyelinated C-fibers in cutaneous peripheral nerves of the African naked-mole rat: a comparative analysis using six species of bathyergidae. J Comp Neurol 520:2785–2803

    Google Scholar 

  • Wu QJ, Tymianski M (2018) Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain 11:15

    CrossRef  Google Scholar 

  • Xiao B, Wang S, Yang G, Sun X, Zhao S, Lin L, Cheng J, Yang W, Cong W, Sun W, Kan G, Cui S (2017) HIF-1α contributes to hypoxia adaptation of the naked mole rat. Oncotarget 8:109941–109951

    CrossRef  Google Scholar 

  • Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, MacDonald JF, Wemmie JA, Price MP, Welsh MJ, Simon RP (2004) Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118:687–698

    CAS  CrossRef  Google Scholar 

Download references

Acknowledgements

We are grateful for the extremely helpful suggestions of two reviewers. We are also grateful for grant support from the National Science Foundation (grant number 0744979 to TJP), a Cancer Research UK/RCUK Multidisciplinary Project Award (C56829/A22053 to ESJS) and ERC advanced grants (AdG 789128 and AdG 294678 to GRL).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas J. Park .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Park, T.J. et al. (2021). African Naked Mole-Rats Demonstrate Extreme Tolerance to Hypoxia and Hypercapnia. In: Buffenstein, R., Park, T.J., Holmes, M.M. (eds) The Extraordinary Biology of the Naked Mole-Rat. Advances in Experimental Medicine and Biology, vol 1319. Springer, Cham. https://doi.org/10.1007/978-3-030-65943-1_9

Download citation