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Mitochondrial functions and melatonin: a tour of the reproductive cancers

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Abstract

Cancers of the reproductive organs have a strong association with mitochondrial defects, and a deeper understanding of the role of this organelle in preneoplastic–neoplastic changes is important to determine the appropriate therapeutic intervention. Mitochondria are involved in events during cancer development, including metabolic and oxidative status, acquisition of metastatic potential, resistance to chemotherapy, apoptosis, and others. Because of their origin from melatonin-producing bacteria, mitochondria are speculated to produce melatonin and its derivatives at high levels; in addition, exogenously administered melatonin accumulates in the mitochondria against a concentration gradient. Melatonin is transported into tumor cell by GLUT/SLC2A and/or by the PEPT1/2 transporters, and plays beneficial roles in mitochondrial homeostasis, such as influencing oxidative phosphorylation and electron flux, ATP synthesis, bioenergetics, calcium influx, and mitochondrial permeability transition pore. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on the main functions of melatonin on mitochondrial processes, and reviews from a mechanistic standpoint, how mitochondrial crosstalk evolved in ovarian, endometrial, cervical, breast, and prostate cancers relative to melatonin’s known actions. We put emphasis on signaling pathways whereby melatonin interferes within cancer-cell mitochondria after its administration. Depending on subtype and intratumor metabolic heterogeneity, melatonin seems to be helpful in promoting apoptosis, anti-proliferation, pro-oxidation, metabolic shifting, inhibiting neovasculogenesis and controlling inflammation, and restoration of chemosensitivity. This results in attenuation of development, progression, and metastatic potential of reproductive cancers, in addition to lowering the risk of recurrence and improving the life quality of patients.

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Acknowledgements

We are grateful to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—Grant number 2016/03993-9) for providing financial support.

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Authors and Affiliations

  1. Department of Anatomy, Institute of Biosciences of Botucatu, UNESP, São Paulo State University, P.O Box: 18618-689, R. Prof. Dr. Antônio Celso Wagner Zanin, 250, Rubião Júnior, Botucatu, SP, Brazil

    Luiz Gustavo de Almeida Chuffa, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira & Luiz Antonio Lupi

  2. Department of Biology and Technology, UENP/CLM, Universidade Estadual do Norte do Paraná, Bandeirantes, Paraná, Brazil

    Fábio Rodrigues Ferreira Seiva

  3. Department of Cellular and Structural Biology, UTHealth, San Antonio, TX, 78229, USA

    Russel J. Reiter

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  1. Luiz Gustavo de Almeida Chuffa
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LGAC, LALJ, HSS, FRFS, and MSC: concept and design of the review and drafted the manuscript. RR: critical revision of the manuscript. All authors significantly contributed with compilation of the literature and approved the final version of the manuscript.

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Correspondence to Luiz Gustavo de Almeida Chuffa.

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de Almeida Chuffa, L.G., Seiva, F.R.F., Cucielo, M.S. et al. Mitochondrial functions and melatonin: a tour of the reproductive cancers. Cell. Mol. Life Sci. 76, 837–863 (2019). https://doi.org/10.1007/s00018-018-2963-0

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