ISSN 0564-3783  

Main page
Information to authors
Editorial board
Mobile version

In Ukrainian

Export citations


Uzun M., Oztopuz R.O., Eroglu H.A., Doganlar O., Doganlar Z.B., M.A. Ovali, Demir U., Buyuk B.


There is increasing awareness that efficient and regular mitochondrial dynamics improves cardiac function and affects the quality of life. Melatonin is the main pineal gland hormone which ameliorates mitochondrial dynamics in many cardiac disorders. For that purpose, we administrated melatonin to healthy rats all day long to investigate a change in left ventricle mitochondrial dynamics both in the end of the nighttime and during daytime.Twenty male Wistar rats (34 months old) were randomly assigned into Control (C; n = 10) and Melatonin groups (MEL; 10 mg/kg melatonin, added to drinking water, n = 10). On the 5th day of the study, 5 rats from the groups were randomly selected and euthanized at 08:00 AM, the remaining 5 rats from each group were euthanized at 20:00 PM, and the samples of left ventricle (LV) tissue were harvested. Quantitative real-time PCR and Western-blot analysis demonstrated that melatonin plays a preventive role on mitochondrial fusion and mitophagy through the DRP1/FIS1 and BNIP3/NIX axis, respectively. Additionally, melatonin administration significantly reduced P21 activation, induced cell cycle arrest, P27, finally regulated caspase- depended mitochondrial apoptosis signals in a time-dependent manner. Our results suggest that melatonin may emerge as a therapeutic candidate to protect the bioenergetic dynamics of mitochondria in heart.

Key words: melatonin, heart, apoptosis, mitochondrial dynamics, mitophagy

Tsitologiya i Genetika 2022, vol. 56, no. 2, pp. 75-77

  1. Faculty of Medicine, Department of Physiology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey
  2. Faculty of Medicine, Department of Biophysics, Çanakkale Onsekiz Mart University, Çanakkale, Turkey
  3. Faculty of Medicine, Department of Medical Biology, Trakya University, Edirne, Turkey
  4. Experimental Research Center, Çanakkale Onsekiz Mart University, Çanakkale, Turkey
  5. Faculty of Medicine, Department of Histology-Embryology, İzmir Democracy University, İzmir, Turkey

E-mail: metehanuzun

Uzun M., Oztopuz R.O., Eroglu H.A., Doganlar O., Doganlar Z.B., M.A. Ovali, Demir U., Buyuk B. MELATONIN IMPROVES LEFT VENTRICULAR MITOCHONDRIAL DYNAMICS IN RATS, Tsitol Genet., 2022, vol. 56, no. 2, pp. 75-77.

In "Cytology and Genetics":
Metehan Uzun, Ozlem Oztopuz, Huseyin Avni Eroglu, Oguzhan Doganlar, Zeynep Banu Doganlar, Mehmet Akif Ovali, Ufuk Demir & Basak Buyuk Melatonin Improves Left Ventricular Mitochondrial Dynamics in Rats, Cytol Genet., 2022, vol. 56, no. 2, pp. 185195
DOI: 10.3103/S0095452722020116


Acuña-Castroviejo, D., Escames, G., Venegas, C., et al., Extrapineal melatonin: sources, regulation, and potential functions, Cell. Mol. Life Sci., 2014, vol. 71, no. 16, pp. 29973025.

Benjamin, E.J., Blaha, M.J., Chiuve, S.E., et al., Heart disease and stroke statistics2017 update: A report from the american heart association, Circulation, 2017, vol. 135, pp. 146603.

Boland, M.L., Chourasia, A.H., and Macleod, K.F., Mitochondrial dysfunction in cancer, Front. Oncol., 2013, vol. 3, art. ID 292.

Canaple, L., Rambaud, J., Dkhissi-Benyahya, O., et al., Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor α defines a novel positive feedback loop in the rodent liver circadian clock, Mol. Endocrinol., 2006, vol. 20, no. 8, pp. 17151727.

Cao, Y., Xu, C., Ye, J., et al., Miro2 Regulates inter-mitochondrial communication in the heart and protects against TAC-induced cardiac dysfunction, Circ. Res., 2019, vol. 125, no. 8, pp. 728743.

Chinnadurai, G., Vijayalingam, S., and Gibson, S.B., BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions, Oncogene, 2008, vol. 27, pp. S114S127.

Coqueret, O., New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment?, Trends Cell Biol., 2003, vol. 13, no. 2, pp. 6570.

Ding, M., Feng, N., Tang, D., et al., Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway, J. Pineal Res., 2018a, vol. 65, no. 2, art. ID e12491.

Ding, M., Ning, J., Feng, N., et al., Dynamin-related protein 1-mediated mitochondrial fission contributes to post-traumatic cardiac dysfunction in rats and the protective effect of melatonin, J. Pineal Res., 2018b, vol. 64, no. 1.

Doll, S., Dreßen, M., Geyer, P.E., et al., Region and cell-type resolved quantitative proteomic map of the human heart, Nat. Commun., 2017, vol. 8, no. 1, art. ID 1469.

Dorn, G.W., Vega, R.B., and Kelly, D.P., Mitochondrial biogenesis and dynamics in the developing and diseased heart, Genes Dev., 2015, vol. 29, no. 19, pp. 19811991.

Eymin, B., Haugg, M., Droin, N., et al., p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells, Oncogene, 1999, vol. 18, no. 7, pp. 14111418.

Gálvez, A.S., Brunskill, E.W., Marreez, Y., et al., Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress, J. Biol. Chem., 2006, vol. 281, no. 3, pp. 14421448.

Gustafsson, A.B., Bnip3 as a dual regulator of mitochondrial turnover and cell death in the myocardium, Pediatr. Cardiol., 2011, vol. 32, no. 3, pp. 267274.

Hamacher-Brady, A. and Brady, N.R., Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy, Cell Mol. Life Sci., 2016, vol. 73, no. 4, 775795.

He, G., Siddik, Z.H., Huang, Z., et al., Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities, Oncogene, 2005, vol. 24, no. 18, pp. 29292943.

Ikeda, Y., Shirakabe, A., Brady, C., et al., Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system, J. Mol. Cell Cardiol., 2015, vol. 78, pp. 116122.

Kim, E.M., Jung, C.H., Kim, J., et al., The p53/p21 complex regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins, Cancer Res., 2017, vol. 77, no. 11, pp. 30923100.

Kohsaka, A., Das, P., Hashimoto, I., et al., The circadian clock maintains cardiac function by regulating mitochondrial metabolism in mice, PLoS One, 2014, vol. 9, no. 11, art. ID e112811.

Li, J., Zheng, X., Ma, X., et al., Melatonin protects against chromium(VI)-induced cardiac injury via activating the AMPK/Nrf2 pathway, J. Inorg. Biochem., 2019, vol. 197, art. ID 110698.

Liu, C., Li, S., Liu, T., et al., Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism, Nature, 2007, vol. 447, no. 7143, pp. 477481.

Lochner, A., Marais, E., and Huisamen, B., Melatonin and cardioprotection against ischaemia/reperfusion injury: Whats new? A review, J. Pineal Res., 2018, vol. 65, no. 1, art. ID e12490.

Marín-García, J. and Akhmedov, A.T., Mitochondrial dynamics and cell death in heart failure, Heart Failure Rev., 2016, vol. 21, no. 2, pp. 123136.

Morales, P.E., Arias-Durán, C., Ávalos-Guajardo, Y., et al., Emerging role of mitophagy in cardiovascular physiology and pathology, Mol. Aspects Med., 2020, vol. 71, art. ID 100822.

Moyzis, A.G., Sadoshima, J., and Gustafsson, Å.B., Mending a broken heart: the role of mitophagy in cardioprotection, Am. J. Physiol.: Heart Circ. Physiol., 2015, vol. 308, no. 3, pp. H183192.

Novak, I., Mitophagy: a complex mechanism of mitochondrial removal, Antioxid. Redox Signal., 2012, vol. 17, no. 5, pp. 794802.

Okamoto, K. and Shaw, J.M., Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes, Annu. Rev. Genet., 2005, vol. 39, pp. 503536.

Ong, S.B, Subrayan, S., Lim, S.Y., et al., Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, Circulation, 2010, vol. 121, no. 18, pp. 20122022.

Ong, S.B., Kalkhoran, S.B., Cabrera-Fuentes, H.A., et al., Mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease, Eur. J. Pharmacol., 2015, vol. 763, pp. 104114.

Otera, H. and Mihara, K., Molecular mechanisms and physiologic functions of mitochondrial dynamics, J. Biochem., 2011, vol. 149, no. 3, pp. 241251.

Papanicolaou, K.N., Kikuchi, R., Ngoh, G.A., et al., Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart, Circ. Res., 2012, vol. 111, no. 8, pp. 10121026.

Paradies, G., Paradies, V., Ruggiero, F.M., et al., Protective role of melatonin in mitochondrial dysfunction and related disorders, Arch. Toxicol., 2015, vol. 89, no. 6, pp. 923939.

Piquereau, J., Caffin, F., Novotova, M., et al., Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload, Cardiovasc. Res., 2012, vol. 94, no. 3, pp. 408417.

Qiu, Z., Wei, Y., Song, Q., et al., The role of myocardial mitochondrial quality control in heart failure, Front. Pharmacol., 2019, vol. 10, art. ID 1404.

Reddy, P.H., Reddy, T.P., Manczak, M., et al., Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases, Brain Res. Rev., 2011, vol. 67, nos. 12, pp. 103-118.

Scott, I. and Youle, R.J., Mitochondrial fission and fusion, Essays Biochem., 2010, vol. 47, pp. 8598.

Tan, D.X., Reiter, R.J., Manchester, L.C., et al., Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger, Curr. Top. Med. Chem., 2002, vol. 2, no. 2, pp. 181197.

Tan, D.X. and Reiter, R.J., Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells, Melatonin Res., 2019, vol. 2, pp. 4466.

Twig, G., Elorza, A., Molina, A.J., et al., Fission and selective fusion govern mitochondrial segregation and elimination by autophagy, EMBO J., 2008, vol. 27, no. 2, pp. 433446.

Vásquez-Trincado, C., García-Carvajal, I., Pennanen, C., et al., Mitochondrial dynamics, mitophagy and cardiovascular disease, J. Physiol., 2016, vol. 594, no. 3, pp. 509525.

Venegas, C., García, J.A., Escames, G., et al., Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations, J. Pineal Res., 2012, vol. 52, no. 2, pp. 217227.

Wang, J., Toan, S., and Zhou, H., Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: New insights into the mechanisms and therapeutic potentials, Pharmacol. Res., 2020, vol. 156, art. ID 104771.

Willich, S.N., Goldberg, R.J., Maclure, M., et al., Increased onset of sudden cardiac death in the first three hours after awakening, Am. J. Cardiol., 1992, vol. 70, no. 1, pp. 6568.

Woltman, A.M., van der Kooij, S.W., Coffer, P.J., et al., Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression, Blood, 2003, vol. 101, no. 4, pp. 14391445.

Youle, R.J. and van der Bliek, A.M., Mitochondrial fission, fusion, and stress, Science, 2012, vol. 337, art. ID 6098, pp. 10621065.

Yussman, M.G., Toyokawa, T., Odley, A., et al., Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy, Nat. Med., 2002, vol. 8, no. 7, pp. 725730.

Zhang, D., and Ma, J., Mitochondrial dynamics in rat heart induced by 5-fluorouracil, Med. Sci. Monit., 2018, vol. 24, pp. 66666672.

Zhang, J. and Ney, P.A., Role of BNIP3 and NIX in cell death, autophagy, and mitophagy, Cell Death Differ., 2009, vol. 16, no. 7, pp. 939946.

Zhang, Y., Liu, D., Hu, H., et al., HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury, Biomed. Pharmacother., 2019a, vol. 120, art. ID 109464.

Zhang, Y., Wang, Y., Xu, J., et al., Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways, J. Pineal Res., 2019b, vol. 66, no. 2, art. ID e12542.

Zhou, H., Wang, S., Hu, S., et al., ER-Mitochondria microdomains in cardiac ischemia-reperfusion injury: a fresh perspective, Front. Physiol., 2018a, vol. 9, art. ID 755.

Zhou, H., Ma, Q., Zhu, P., et al., Protective role of melatonin in cardiac ischemia-reperfusion injury: from pathogenesis to targeted therapy, J. Pineal Res., 2018b, vol. 64, no. 3.

Copyright© ICBGE 2002-2023 Coded & Designed by Volodymyr Duplij Modified 31.01.23