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Melatonin, clock genes and mitochondria in sepsis

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Abstract

After the characterization of the central pacemaker in the suprachiasmatic nucleus, the expression of clock genes was identified in several peripheral tissues including the immune system. The hierarchical control from the central clock to peripheral clocks extends to other functions including endocrine, metabolic, immune, and mitochondrial responses. Increasing evidence links the disruption of the clock genes expression with multiple diseases and aging. Chronodisruption is associated with alterations of the immune system, immunosenescence, impairment of energy metabolism, and reduction of pineal and extrapineal melatonin production. Regarding sepsis, a condition coursing with an exaggerated response of innate immunity, experimental and clinical data showed an alteration of circadian rhythms that reflects the loss of the normal oscillation of the clock. Moreover, recent data point to that some mediators of the immune system affects the normal function of the clock. Under specific conditions, this control disappears reactivating the immune response. So, it seems that clock gene disruption favors the innate immune response, which in turn induces the expression of proinflammatory mediators, causing a further alteration of the clock. Here, the clock control of the mitochondrial function turns off, leading to a bioenergetic decay and formation of reactive oxygen species that, in turn, activate the inflammasome. This arm of the innate immunity is responsible for the huge increase of interleukin-1β and entrance into a vicious cycle that could lead to the death of the patient. The broken clock is recovered by melatonin administration, that is accompanied by the normalization of the innate immunity and mitochondrial homeostasis. Thus, this review emphasizes the connection between clock genes, innate immunity and mitochondria in health and sepsis, and the role of melatonin to maintain clock homeostasis.

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Acknowledgements

This study was partially supported by Grants from the Ministerio de Economía, Industria y Competitividad, y por el Fondo de Desarrollo Regional FEDER, Spain # RD12/0043/0005; PI13-00981; PI16-00519; PI16-00CB16-10-00238), and from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P07-CTS-03135, P10-CTS-5784, and CTS-101), Spain. CA-F is a Resident Medical Intern, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain; MF-O is supported by a FPU fellowship from the Ministerio de Educación, Cultura y Deporte, Spain; MED-C is supported by a postdoctoral fellowship from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain, and LCL is supported by the “Ramón y Cajal” National Program (Ministerio de Economía y Competitividad, Spain).

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Authors and Affiliations

  1. Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avenida del Conocimiento s/n, 18016, Granada, Spain

    Darío Acuña-Castroviejo, Ibtissem Rahim, Marisol Fernández-Ortiz, Ramy K. A. Sayed, María E. Díaz-Casado, Iryna Rusanova, Luis C. López & Germaine Escames

  2. CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain

    Darío Acuña-Castroviejo, Iryna Rusanova, Luis C. López & Germaine Escames

  3. Département de Biologie et Physiologie Cellulaire, Faculté des Sciences de la Nature et de la Vie, Université Blida 1, Blida, Algeria

    Ibtissem Rahim

  4. Unidad of Anestesiología y Reanimación, Hospital Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain

    Carlos Acuña-Fernández & Jorge Solera-Marín

  5. Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohâg, Egypt

    Ramy K. A. Sayed

Authors
  1. Darío Acuña-Castroviejo
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  2. Ibtissem Rahim
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  3. Carlos Acuña-Fernández
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  4. Marisol Fernández-Ortiz
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  5. Jorge Solera-Marín
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  6. Ramy K. A. Sayed
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  7. María E. Díaz-Casado
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  8. Iryna Rusanova
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  9. Luis C. López
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  10. Germaine Escames
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Corresponding author

Correspondence to Darío Acuña-Castroviejo.

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Acuña-Castroviejo, D., Rahim, I., Acuña-Fernández, C. et al. Melatonin, clock genes and mitochondria in sepsis. Cell. Mol. Life Sci. 74, 3965–3987 (2017). https://doi.org/10.1007/s00018-017-2610-1

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  • DOI: https://doi.org/10.1007/s00018-017-2610-1

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