Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial Reactive Oxygen Species Elicit Acute and Chronic Itch via Transient Receptor Potential Canonical 3 Activation in Mice

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Mitochondrial reactive oxygen species (mROS) that are overproduced by mitochondrial dysfunction are linked to pathological conditions including sensory abnormalities. Here, we explored whether mROS overproduction induces itch through transient receptor potential canonical 3 (TRPC3), which is sensitive to ROS. Intradermal injection of antimycin A (AA), a selective inhibitor of mitochondrial electron transport chain complex III for mROS overproduction, produced robust scratching behavior in naïve mice, which was suppressed by MitoTEMPO, a mitochondria-selective ROS scavenger, and Pyr10, a TRPC3-specific blocker, but not by blockers of TRPA1 or TRPV1. AA activated subsets of trigeminal ganglion neurons and also induced inward currents, which were blocked by MitoTEMPO and Pyr10. Besides, dry skin-induced chronic scratching was relieved by MitoTEMPO and Pyr10, and also by resveratrol, an antioxidant. Taken together, our results suggest that mROS elicit itch through TRPC3, which may underlie chronic itch, representing a potential therapeutic target for chronic itch.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell 2012, 48: 158–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gopčević KR, Rovčanin BR, Tatić SB, Krivokapić ZV, Gajić MM, Dragutinović VV. Activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in different stages of colorectal carcinoma. Dig Dis Sci 2013, 58: 2646–2652.

    Article  PubMed  CAS  Google Scholar 

  3. Bonawitz ND, Rodeheffer MS, Shadel GS. Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. Mol Cell Biol 2006, 26: 4818–4829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443: 787–795.

    Article  CAS  PubMed  Google Scholar 

  5. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell 2012, 148: 1145–1159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Holmström KM, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 2014, 15: 411–421.

    Article  PubMed  CAS  Google Scholar 

  7. Nesuashvili L, Hadley SH, Bahia PK, Taylor-Clark TE. Sensory nerve terminal mitochondrial dysfunction activates airway sensory nerves via transient receptor potential (TRP) channels. Mol Pharmacol 2013, 83: 1007–1019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hadley SH, Bahia PK, Taylor-Clark TE. Sensory nerve terminal mitochondrial dysfunction induces hyperexcitability in airway nociceptors via protein kinase C. Mol Pharmacol 2014, 85: 839–848.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kim HY, Lee KY, Lu Y, Wang JG, Cui L, Kim SJ. Mitochondrial Ca2+ uptake is essential for synaptic plasticity in pain. J Neurosci 2011, 31: 12982–12991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sui BD, Xu TQ, Liu JW, Wei W, Zheng CX, Guo BL, et al. Understanding the role of mitochondria in the pathogenesis of chronic pain. Postgrad Med J 2013, 89: 709–714.

    Article  CAS  PubMed  Google Scholar 

  11. Kim HY, Chung JM, Chung K. Increased production of mitochondrial superoxide in the spinal cord induces pain behaviors in mice: The effect of mitochondrial electron transport complex inhibitors. Neurosci Lett 2008, 447: 87–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Joseph EK, Levine JD. Mitochondrial electron transport in models of neuropathic and inflammatory pain. Pain 2006, 121: 105–114.

    Article  CAS  PubMed  Google Scholar 

  13. LaMotte RH, Dong XZ, Ringkamp M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci 2014, 15: 19–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ward L, Wright E, McMahon SB. A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain 1996, 64: 129–138.

    Article  PubMed  Google Scholar 

  15. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science 2009, 325: 1531–1534.

    Article  CAS  PubMed  Google Scholar 

  16. Dong XT, Dong XZ. Peripheral and central mechanisms of itch. Neuron 2018, 98: 482–494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xiao BL, Patapoutian A. Scratching the surface: A role of pain-sensing TRPA1 in itch. Nat Neurosci 2011, 14: 540–542.

    Article  CAS  PubMed  Google Scholar 

  18. Ogawa N, Kurokawa T, Mori YS. Sensing of redox status by TRP channels. Cell Calcium 2016, 60: 115–122.

    Article  CAS  PubMed  Google Scholar 

  19. Poteser M, Graziani A, Rosker C, Eder P, Derler I, Kahr H, et al. TRPC3 and TRPC4 associate to form a redox-sensitive cation channel. J Biol Chem 2006, 281: 13588–13595.

    Article  CAS  PubMed  Google Scholar 

  20. Cioffi DL. Redox regulation of endothelial canonical transient receptor potential channels. Antioxid Redox Signal 2011, 15: 1567–1582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Balzer M, Lintschinger B, Groschner K. Evidence for a role of Trp proteins in the oxidative stress-induced membrane conductances of porcine aortic endothelial cells. Cardiovasc Res 1999, 42: 543–549.

    Article  CAS  PubMed  Google Scholar 

  22. Luo WQ, Wickramasinghe SR, Savitt JM, Griffin JW, Dawson TM, Ginty DD. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron 2007, 54: 739–754.

    Article  CAS  PubMed  Google Scholar 

  23. Alkhani H, Ase AR, Grant R, O’Donnell D, Groschner K, Séguéla P. Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors. Mol Pain 2014, 10: 43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou DH, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci 2015, 18: 145–153.

    Article  CAS  PubMed  Google Scholar 

  25. Than JYXL, Li L, Hasan R, Zhang XM. Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine. J Biol Chem 2013, 288: 12818–12827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens DM, et al. The ion channel TRPA1 is required for chronic itch. J Neurosci 2013, 33: 9283–9294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pelizzoni I, Macco R, Morini MF, Zacchetti D, Grohovaz F, Codazzi F. Iron handling in hippocampal neurons: Activity-dependent iron entry and mitochondria-mediated neurotoxicity. Aging Cell 2011, 10: 172–183.

    Article  CAS  PubMed  Google Scholar 

  28. Schleifer H, Doleschal B, Lichtenegger M, Oppenrieder R, Derler I, Frischauf I, et al. Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca2+ entry pathways. Br J Pharmacol 2012, 167: 1712–1722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, et al. TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci USA 2007, 104: 13525–13530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gavva NR, Tamir R, Qu YS, Klionsky L, Zhang TJ, Immke D, et al. AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2, 3-dihydrobenzo[b][1, 4]dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 2005, 313: 474–484.

    Article  CAS  PubMed  Google Scholar 

  31. Price NL, Gomes AP, Ling AJY, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 2012, 15: 675–690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shimada SG, LaMotte RH. Behavioral differentiation between itch and pain in mouse. Pain 2008, 139: 681–687.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ehling S, Butler A, Thi S, Ghashghaei HT, Bäumer W. To scratch an itch: Establishing a mouse model to determine active brain areas involved in acute histaminergic itch. IBRO Rep 2018, 5: 67–73.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Park CK, Kim MS, Fang Z, Li HY, Jung SJ, Choi SY, et al. Functional expression of thermo-transient receptor potential channels in dental primary afferent neurons. J Biol Chem 2006, 281: 17304–17311.

    Article  CAS  PubMed  Google Scholar 

  35. Turrens JF, Alexandre A, Lehninger AL. Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 1985, 237: 408–414.

    Article  CAS  PubMed  Google Scholar 

  36. Vesce S, Kirk L, Nicholls DG. Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate. J Neurochem 2004, 90: 683–693.

    Article  CAS  PubMed  Google Scholar 

  37. Green AD, Young KK, Lehto SG, Smith SB, Mogil JS. Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain 2006, 124: 50–58.

    Article  CAS  PubMed  Google Scholar 

  38. Liu Q, Tang ZX, Surdenikova L, Kim S, Patel KN, Kim A, et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 2009, 139: 1353–1365.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci 2010, 13: 1460–1462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu T, Ji RR. Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci Bull 2012, 28: 145–154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Grundmann S, Ständer S. Chronic pruritus: Clinics and treatment. Ann Dermatol 2011, 23: 1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hung KS, Hertweck MS, Hardy JD, Loosli CG. Ultrastructure of nerves and associated cells in bronchiolar epithelium of the mouse lung. J Ultrastruct Res 1973, 43: 426–437.

    Article  CAS  PubMed  Google Scholar 

  43. Sivaranjani N, Rao SV, Rajeev G. Role of reactive oxygen species and antioxidants in atopic dermatitis. J Clin Diagn Res 2013, 7: 2683–2685.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Alexandre A, Lehninger AL. Bypasses of the antimycin a block of mitochondrial electron transport in relation to ubisemiquinone function. Biochim Biophys Acta 1984, 767: 120–129.

    Article  CAS  PubMed  Google Scholar 

  45. Carr WJ, Oberley-Deegan RE, Zhang YP, Oberley CC, Oberley LW, Dunnwald M. Antioxidant proteins and reactive oxygen species are decreased in a murine epidermal side population with stem cell-like characteristics. Histochem Cell Biol 2011, 135: 293–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Joseph EK, Levine JD. Multiple PKCε-dependent mechanisms mediating mechanical hyperalgesia. Pain 2010, 150: 17–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Joseph EK, Levine JD. Comparison of oxaliplatin- and cisplatin-induced painful peripheral neuropathy in the rat. J Pain 2009, 10: 534–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gonzalez-Dosal R, Horan KA, Paludan SR. Mitochondria-derived reactive oxygen species negatively regulates immune innate signaling pathways triggered by a DNA virus, but not by an RNA virus. Biochem Biophys Res Commun 2012, 418: 806–810.

    Article  CAS  PubMed  Google Scholar 

  49. Liu M, Liu H, Dudley SC Jr. Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel. Circ Res 2010, 107: 967–974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee SH, Cho PS, Tonello R, Lee HK, Jang JH, Park GY, et al. Peripheral serotonin receptor 2B and transient receptor potential channel 4 mediate pruritus to serotonergic antidepressants in mice. J Allergy Clin Immunol 2018, 142: 1349-1352.e16.

    Article  CAS  PubMed  Google Scholar 

  51. Sun SH, Dong XZ. Trp channels and itch. Semin Immunopathol 2016, 38: 293–307.

    Article  PubMed  Google Scholar 

  52. Dong P, Guo CX, Huang SX, Ma MH, Liu Q, Luo WQ. TRPC3 is dispensable for β-alanine triggered acute itch. Sci Rep 2017, 7: 13869.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Takahashi N, Mori YS. TRP channels as sensors and signal integrators of redox status changes. Front Pharmacol 2011, 2: 58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci 2006, 7: 535–547.

    Article  CAS  PubMed  Google Scholar 

  55. Dixon AD. The ultrastructure of nerve fibers in the trigeminal ganglion of the rat. J Ultrastruct Res 1963, 8: 107–121.

    Article  CAS  PubMed  Google Scholar 

  56. Molliver DC, Radeke MJ, Feinstein SC, Snider WD. Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections. J Comp Neurol 1995, 361: 404–416.

    Article  CAS  PubMed  Google Scholar 

  57. Snider WD, McMahon SB. Tackling pain at the source: New ideas about nociceptors. Neuron 1998, 20: 629–632.

    Article  CAS  PubMed  Google Scholar 

  58. Han L, Ma C, Liu Q, Weng HJ, Cui YY, Tang ZX, et al. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 2013, 16: 174–182.

    Article  CAS  PubMed  Google Scholar 

  59. Liu Q, Sikand P, Ma C, Tang ZX, Han L, Li Z, et al. Mechanisms of itch evoked by β-alanine. J Neurosci 2012, 32: 14532–14537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim BM, Lee SH, Shim WS, Oh U. Histamine-induced Ca2+ influx via the PLA2/lipoxygenase/TRPV1 pathway in rat sensory neurons. Neurosci Lett 2004, 361: 159–162.

    Article  CAS  PubMed  Google Scholar 

  61. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong XZ, et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011, 14: 595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kittaka H, Tominaga M. The molecular and cellular mechanisms of itch and the involvement of TRP channels in the peripheral sensory nervous system and skin. Allergol Int 2017, 66: 22–30.

    Article  CAS  PubMed  Google Scholar 

  63. Giorgi S, Nikolaeva-Koleva M, Alarcón-Alarcón D, Butrón L, González-Rodríguez S. Is TRPA1 Burning down TRPV1 as druggable target for the treatment of chronic pain? Int J Mol Sci 2019, 20: E2906.

    Article  PubMed  CAS  Google Scholar 

  64. Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 2006, 126: 2565–2575.

    Article  CAS  PubMed  Google Scholar 

  65. Feichtinger RG, Sperl W, Bauer JW, Kofler B. Mitochondrial dysfunction: A neglected component of skin diseases. Exp Dermatol 2014, 23: 607–614.

    Article  CAS  PubMed  Google Scholar 

  66. Mela M, Mancuso A, Burroughs AK. Review article: Pruritus in cholestatic and other liver diseases. Aliment Pharmacol Ther 2003, 17: 857–870.

    Article  CAS  PubMed  Google Scholar 

  67. Weisshaar E, Dalgard F. Epidemiology of itch: Adding to the burden of skin morbidity. Acta Derm Venereol 2009, 89: 339–350.

    Article  PubMed  Google Scholar 

  68. Carstens E, Akiyama T. Neuropathic itch—itch: Mechanisms and treatment. 2014. CRC Press/Taylor & Francis, 2014.

  69. Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest 2013, 123: 951–957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zylka MJ, Rice FL, Anderson DJ. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 2005, 45: 17–25.

    Article  CAS  PubMed  Google Scholar 

  71. Valtcheva MV, Samineni VK, Golden JP, Gereau RW 4th, Davidson S. Enhanced nonpeptidergic intraepidermal fiber density and an expanded subset of chloroquine-responsive trigeminal neurons in a mouse model of dry skin itch. J Pain 2015, 16: 346–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kwan HY, Wong CO, Chen ZY, Chan TWD, Huang Y, Yao XQ. Stimulation of histamine H2 receptors activates TRPC3 channels through both phospholipase C and phospholipase D. Eur J Pharmacol 2009, 602: 181–187.

    Article  CAS  PubMed  Google Scholar 

  73. Zhou FM, Lee CR. Intrinsic and integrative properties of substantia nigra pars reticulata neurons. Neuroscience 2011, 198: 69–94.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Justin C. Lee for the kind gift of TRPA1-KO mice and Alexander J. Davies for valuable comments on the manuscript. This research was supported by the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2018R1A5A2024418 and NRF-2021R1A2C3003334) and the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2020R1I1A1A01068037).

Author information

Author notes

  1. Seong-Ah Kim and Jun Ho Jang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology and Physiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea

    Seong-Ah Kim, Jun Ho Jang, Pa Reum Lee, Hue Vang & Seog Bae Oh

  2. Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    Wheedong Kim

  3. Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea

    Yong Ho Kim

  4. Tooth-Periodontium Complex Medical Research Center, School of Dentistry, Seoul National University, Seoul, 03080, Republic of Korea

    Kihwan Lee & Seog Bae Oh

Authors
  1. Seong-Ah Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Ho Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wheedong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pa Reum Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Ho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hue Vang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kihwan Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seog Bae Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kihwan Lee or Seog Bae Oh.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 418 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, SA., Jang, J.H., Kim, W. et al. Mitochondrial Reactive Oxygen Species Elicit Acute and Chronic Itch via Transient Receptor Potential Canonical 3 Activation in Mice. Neurosci. Bull. 38, 373–385 (2022). https://doi.org/10.1007/s12264-022-00837-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-022-00837-6

Keywords

Search

Navigation