Evaluation of Serum Humanin and MOTS-c Peptide Levels in Patients
with COVID-19 and Healthy Subjects

Ahmet      Saracaloglu; Ayşe   Özlem   Mete; Duran   Furkan   Ucar; Seniz      Demiryürek; Enes      Erbagcı; Abdullah   Tuncay   Demiryürek

doi:10.2174/1389203724666230217101202

Abstract

Background: Coronavirus Disease 2019 (COVID-19) is a life-threatening and persistent pandemic with high rates of mortality and morbidity. Although a dysfunction in the mitochondria occurs in COVID-19 pathogenesis, the contribution of mitochondrial-derived peptides to its pathophysiology has not yet been completely elucidated. The goals of this research were to assess the circulating humanin and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) levels in COVID-19 patients and explore the effects of antiviral drug therapy on these peptide levels.

Methods: Thirty adult COVID-19 patients and 32 gender-matched healthy volunteers were enrolled in this study. Circulating humanin and MOTS-c levels were detected using the ELISA method during pretreatment (before drug therapy) and post-treatment (on the 7th day of drug therapy).

Results: We found that there was significant attenuation of the serum humanin levels in COVID-19 patients (P < 0.001). However, we detected a significant augmentation in serum MOTS-c levels when compared to controls (P < 0.01 for pre-treatment and P < 0.001 for post-treatment). Interestingly, antiviral drug therapy did not modify the serum MOTS-c and humanin levels.

Conclusion: Our findings suggest that MOTS-c and humanin were involved in the COVID-19 pathogenesis. Our data may also imply that elevated MOTS-c could act as a compensatory mechanism to eliminate the effects of decreased humanin levels.

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[1]
WHO. WHO Coronavirus (COVID-19) Dashboard. 2022. Available from: https://covid19.who.int

[2]
Saleh, J.; Peyssonnaux, C.; Singh, K.K.; Edeas, M. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion,  2020, 54, 1-7.
 [http://dx.doi.org/10.1016/j.mito.2020.06.008] [PMID:  32574708]

[3]
Wang, L.; Wu, Q.; Fan, Z.; Xie, R.; Wang, Z.; Lu, Y. Platelet mitochondrial dysfunction and the correlation with human diseases. Biochem. Soc. Trans.,  2017, 45(6), 1213-1223.
 [http://dx.doi.org/10.1042/BST20170291] [PMID:  29054925]

[4]
Rochette, L.; Meloux, A.; Zeller, M.; Cottin, Y.; Vergely, C. Role of humanin, a mitochondrial-derived peptide, in cardiovascular disorders. Arch. Cardiovasc. Dis.,  2020, 113(8-9), 564-571.
 [http://dx.doi.org/10.1016/j.acvd.2020.03.020] [PMID:  32680738]

[5]
Hashimoto, Y.; Ito, Y.; Niikura, T.; Shao, Z.; Hata, M.; Oyama, F.; Nishimoto, I. Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein. Biochem. Biophys. Res. Commun.,  2001, 283(2), 460-468.
 [http://dx.doi.org/10.1006/bbrc.2001.4765] [PMID:  11327724]

[6]
Rochette, L.; Rigal, E.; Dogon, G.; Malka, G.; Zeller, M.; Vergely, C.; Cottin, Y. Mitochondrial-derived peptides: New markers for cardiometabolic dysfunction. Arch. Cardiovasc. Dis.,  2022, 115(1), 48-56.
 [http://dx.doi.org/10.1016/j.acvd.2021.10.013] [PMID:  34972639]

[7]
Zhu, S.; Hu, X.; Bennett, S.; Xu, J.; Mai, Y. The molecular structure and role of humanin in neural and skeletal diseases, and in tissue regeneration. Front. Cell Dev. Biol.,  2022, 10, 823354.
 [http://dx.doi.org/10.3389/fcell.2022.823354] [PMID:  35372353]

[8]
Kim, S.J.; Miller, B.; Kumagai, H.; Silverstein, A.R.; Flores, M.; Yen, K. Mitochondrial-derived peptides in aging and age-related diseases. Geroscience,  2021, 43(3), 1113-1121.
 [http://dx.doi.org/10.1007/s11357-020-00262-5] [PMID:  32910336]

[9]
Zuccato, C.F.; Asad, A.S.; Nicola Candia, A.J.; Gottardo, M.F.; Moreno Ayala, M.A.; Theas, M.S.; Seilicovich, A.; Candolfi, M. Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases. Expert Opin. Ther. Targets,  2019, 23(2), 117-126.
 [http://dx.doi.org/10.1080/14728222.2019.1559300] [PMID:  30582721]

[10]
Hazafa, A.; Batool, A.; Ahmad, S.; Amjad, M.; Chaudhry, S.N.; Asad, J.; Ghuman, H.F.; Khan, H.M.; Naeem, M.; Ghani, U. Humanin: A mitochondrial-derived peptide in the treatment of apoptosis-related diseases. Life Sci.,  2021, 264, 118679.
 [http://dx.doi.org/10.1016/j.lfs.2020.118679] [PMID:  33130077]

[11]
Kim, S.J.; Devgan, A.; Miller, B.; Lee, S.M.; Kumagai, H.; Wilson, K.A.; Wassef, G.; Wong, R.; Mehta, H.H.; Cohen, P.; Yen, K. Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension. Biochim. Biophys. Acta, Gen. Subj.,  2022, 1866(1), 130017.
 [http://dx.doi.org/10.1016/j.bbagen.2021.130017] [PMID:  34624450]

[12]
Ramanjaneya, M.; Bettahi, I.; Jerobin, J.; Chandra, P.; Abi Khalil, C.; Skarulis, M.; Atkin, S.L.; Abou-Samra, A.B. Mitochondrial-derived peptides are down regulated in diabetes subjects. Front. Endocrinol.,  2019, 10, 331.
 [http://dx.doi.org/10.3389/fendo.2019.00331] [PMID:  31214116]

[13]
Widmer, R.J.; Flammer, A.J.; Herrmann, J.; Rodriguez-Porcel, M.; Wan, J.; Cohen, P.; Lerman, L.O.; Lerman, A. Circulating humanin levels are associated with preserved coronary endothelial function. Am. J. Physiol. Heart Circ. Physiol.,  2013, 304(3), H393-H397.
 [http://dx.doi.org/10.1152/ajpheart.00765.2012] [PMID:  23220334]

[14]
Lee, C.; Zeng, J.; Drew, B.G.; Sallam, T.; Martin-Montalvo, A.; Wan, J.; Kim, S.J.; Mehta, H.; Hevener, A.L.; de Cabo, R.; Cohen, P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab.,  2015, 21(3), 443-454.
 [http://dx.doi.org/10.1016/j.cmet.2015.02.009] [PMID:  25738459]

[15]
D’Souza, R.F.; Woodhead, J.S.T.; Hedges, C.P.; Zeng, N.; Wan, J.; Kumagai, H.; Lee, C.; Cohen, P.; Cameron-Smith, D.; Mitchell, C.J.; Merry, T.L. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY),  2020, 12(6), 5244-5258.
 [http://dx.doi.org/10.18632/aging.102944] [PMID:  32182209]

[16]
García-Benlloch, S.; Revert-Ros, F.; Blesa, J.R.; Alis, R. MOTS-c promotes muscle differentiation in vitro. Peptides,  2022, 155, 170840.
 [http://dx.doi.org/10.1016/j.peptides.2022.170840] [PMID:  35842023]

[17]
Cataldo, L.R.; Fernández-Verdejo, R.; Santos, J.L.; Galgani, J.E. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J. Investig. Med.,  2018, 66(6), 1019-1022.
 [http://dx.doi.org/10.1136/jim-2017-000681] [PMID:  29593067]

[18]
Qin, Q.; Delrio, S.; Wan, J.; Jay Widmer, R.; Cohen, P.; Lerman, L.O.; Lerman, A. Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. Int. J. Cardiol.,  2018, 254, 23-27.
 [http://dx.doi.org/10.1016/j.ijcard.2017.12.001] [PMID:  29242099]

[19]
Laforge, M.; Elbim, C.; Frère, C.; Hémadi, M.; Massaad, C.; Nuss, P.; Benoliel, J.J.; Becker, C. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat. Rev. Immunol.,  2020, 20(9), 515-516.
 [http://dx.doi.org/10.1038/s41577-020-0407-1] [PMID:  32728221]

[20]
Kumar, A.; Arora, A.; Sharma, P.; Anikhindi, S.A.; Bansal, N.; Singla, V.; Khare, S.; Srivastava, A. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab. Syndr.,  2020, 14(4), 535-545.
 [http://dx.doi.org/10.1016/j.dsx.2020.04.044] [PMID:  32408118]

[21]
Mete, A.Ö.; Koçak, K.; Saracaloglu, A.; Demiryürek, S.; Altınbaş, Ö.; Demiryürek, A.T. Effects of antiviral drug therapy on dynamic thiol/disulphide homeostasis and nitric oxide levels in COVID-19 patients. Eur. J. Pharmacol.,  2021, 907, 174306.
 [http://dx.doi.org/10.1016/j.ejphar.2021.174306] [PMID:  34245744]

[22]
Bachar, A.R.; Scheffer, L.; Schroeder, A.S.; Nakamura, H.K.; Cobb, L.J.; Oh, Y.K.; Lerman, L.O.; Pagano, R.E.; Cohen, P.; Lerman, A. Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc. Res.,  2010, 88(2), 360-366.
 [http://dx.doi.org/10.1093/cvr/cvq191] [PMID:  20562421]

[23]
Peluso, M.J.; Deeks, S.G.; Mustapic, M.; Kapogiannis, D.; Henrich, T.J.; Lu, S.; Goldberg, S.A.; Hoh, R.; Chen, J.Y.; Martinez, E.O.; Kelly, J.D.; Martin, J.N.; Goetzl, E.J. SARS‐CoV‐2 and mitochondrial proteins in neural‐derived exosomes of COVID‐19. Ann. Neurol.,  2022, 91(6), 772-781.
 [http://dx.doi.org/10.1002/ana.26350] [PMID:  35285072]

[24]
Valdés-Aguayo, J.J.; Garza-Veloz, I.; Vargas-Rodríguez, J.R.; Martinez-Vazquez, M.C.; Avila-Carrasco, L.; Bernal-Silva, S.; González-Fuentes, C.; Comas-García, A.; Alvarado-Hernández, D.E.; Centeno-Ramirez, A.S.H.; Rodriguez-Sánchez, I.P.; Delgado-Enciso, I.; Martinez-Fierro, M.L. Peripheral blood mitochondrial DNA levels were modulated by SARS-CoV-2 infection severity and its lessening was associated with mortality among hospitalized patients with COVID-19. Front. Cell. Infect. Microbiol.,  2021, 11, 754708.
 [http://dx.doi.org/10.3389/fcimb.2021.754708] [PMID:  34976854]

[25]
Streng, L.W.J.M.; de Wijs, C.J.; Raat, N.J.H.; Specht, P.A.C.; Sneiders, D.; van der Kaaij, M.; Endeman, H.; Mik, E.G.; Harms, F.A. In vivo and ex vivo mitochondrial function in COVID-19 patients on the intensive care unit. Biomedicines,  2022, 10(7), 1746.
 [http://dx.doi.org/10.3390/biomedicines10071746] [PMID:  35885051]

[26]
Shang, C.; Liu, Z.; Zhu, Y.; Lu, J.; Ge, C.; Zhang, C.; Li, N.; Jin, N.; Li, Y.; Tian, M.; Li, X. SARS-CoV-2 causes mitochondrial dysfunction and mitophagy impairment. Front. Microbiol.,  2022, 12, 780768.
 [http://dx.doi.org/10.3389/fmicb.2021.780768] [PMID:  35069483]

[27]
Merry, T.L.; Chan, A.; Woodhead, J.S.T.; Reynolds, J.C.; Kumagai, H.; Kim, S.J.; Lee, C. Mitochondrial-derived peptides in energy metabolism. Am. J. Physiol. Endocrinol. Metab.,  2020, 319(4), E659-E666.
 [http://dx.doi.org/10.1152/ajpendo.00249.2020] [PMID:  32776825]

[28]
Ambrosino, P.; Calcaterra, I.L.; Mosella, M.; Formisano, R.; D’Anna, S.E.; Bachetti, T.; Marcuccio, G.; Galloway, B.; Mancini, F.P.; Papa, A.; Motta, A.; Di Minno, M.N.D.; Maniscalco, M. Endothelial dysfunction in COVID-19: A unifying mechanism and a potential therapeutic target. Biomedicines,  2022, 10(4), 812.
 [http://dx.doi.org/10.3390/biomedicines10040812] [PMID:  35453563]

[29]
Yang, Y.; Gao, H.; Zhou, H.; Liu, Q.; Qi, Z.; Zhang, Y.; Zhang, J. The role of mitochondria-derived peptides in cardiovascular disease: Recent updates. Biomed. Pharmacother.,  2019, 117, 109075.
 [http://dx.doi.org/10.1016/j.biopha.2019.109075] [PMID:  31185388]

[30]
Ma, Z.; Liu, D. Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins. Acta Pharmacol. Sin.,  2018, 39(6), 1012-1021.
 [http://dx.doi.org/10.1038/aps.2017.169] [PMID:  29265109]

[31]
Yen, K.; Lee, C.; Mehta, H.; Cohen, P. The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J. Mol. Endocrinol.,  2013, 50(1), R11-R19.
 [http://dx.doi.org/10.1530/JME-12-0203] [PMID:  23239898]

[32]
Matsunaga, D.; Sreekumar, P.G.; Ishikawa, K.; Terasaki, H.; Barron, E.; Cohen, P.; Kannan, R.; Hinton, D.R. Humanin protects RPE cells from endoplasmic reticulum stress-induced apoptosis by upregulation of mitochondrial glutathione. PLoS One,  2016, 11(10)e0165150
 [http://dx.doi.org/10.1371/journal.pone.0165150] [PMID:  27783653]

[33]
Minasyan, L.; Sreekumar, P.G.; Hinton, D.R.; Kannan, R. Protective mechanisms of the mitochondrial-derived peptide humanin in oxidative and endoplasmic reticulum stress in RPE cells. Oxid. Med. Cell. Longev.,  2017, 2017, 1-11.
 [http://dx.doi.org/10.1155/2017/1675230] [PMID:  28814984]

[34]
Yang, B.; Yu, Q.; Chang, B.; Guo, Q.; Xu, S.; Yi, X.; Cao, S. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway. Biochim. Biophys. Acta Mol. Basis Dis.,  2021, 1867(6), 166126.
 [http://dx.doi.org/10.1016/j.bbadis.2021.166126] [PMID:  33722744]

[35]
Li, H.; Ren, K.; Jiang, T.; Zhao, G.J. MOTS-c attenuates endothelial dysfunction via suppressing the MAPK/NF-κB pathway. Int. J. Cardiol.,  2018, 268, 40.
 [http://dx.doi.org/10.1016/j.ijcard.2018.03.031] [PMID:  30041797]

[36]
Shen, C.; Wang, J.; Feng, M.; Peng, J.; Du, X.; Chu, H.; Chen, X. The mitochondrial-derived peptide MOTS-c attenuates oxidative stress injury and the inflammatory response of H9c2 cells through the Nrf2/ARE and NF-κB pathways. Cardiovasc. Eng. Technol.,  2021, 1-1.
 [http://dx.doi.org/10.1007/s13239-021-00589-w] [PMID:  34859377]

[37]
Wei, M.; Gan, L.; Liu, Z.; Liu, L.; Chang, J.R.; Yin, D.C.; Cao, H.L.; Su, X.L.; Smith, W.W. Mitochondrial-derived peptide MOTS-c attenuates vascular calcification and secondary myocardial remodeling via adenosine monophosphate-activated protein kinase signaling pathway. Cardiorenal Med.,  2020, 10(1), 42-50.
 [http://dx.doi.org/10.1159/000503224] [PMID:  31694019]

[38]
Wiernsperger, N.; Al-Salameh, A.; Cariou, B.; Lalau, J.D. Protection by metformin against severe Covid-19: An in-depth mechanistic analysis. Diabetes Metab.,  2022, 48(4), 101359.
 [http://dx.doi.org/10.1016/j.diabet.2022.101359] [PMID:  35662580]

[39]
Dërmaku-Sopjani, M.; Sopjani, M. Interactions between ACE2 and SARS-CoV-2 S Protein: Peptide inhibitors for potential drug developments against COVID-19. Curr. Protein Pept. Sci.,  2021, 22(10), 729-744.
 [http://dx.doi.org/10.2174/1389203722666210916141924] [PMID:  34530706]

[40]
Lei, Y.; Zhang, J.; Schiavon, C.R.; He, M.; Chen, L.; Shen, H.; Zhang, Y.; Yin, Q.; Cho, Y.; Andrade, L.; Shadel, G.S.; Hepokoski, M.; Lei, T.; Wang, H.; Zhang, J.; Yuan, J.X.J.; Malhotra, A.; Manor, U.; Wang, S.; Yuan, Z.Y.; Shyy, J.Y.J. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ. Res.,  2021, 128(9), 1323-1326.
 [http://dx.doi.org/10.1161/CIRCRESAHA.121.318902] [PMID:  33784827]

[41]
Hariyanto, T.I.; Kurniawan, A. Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection. Obes. Med.,  2020, 19, 100290.
 [http://dx.doi.org/10.1016/j.obmed.2020.100290] [PMID:  32844132]

[42]
Appelberg, S.; Gupta, S.; Svensson Akusjärvi, S.; Ambikan, A.T.; Mikaeloff, F.; Saccon, E.; Végvári, Á.; Benfeitas, R.; Sperk, M.; Ståhlberg, M.; Krishnan, S.; Singh, K.; Penninger, J.M.; Mirazimi, A.; Neogi, U. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg. Microbes Infect.,  2020, 9(1), 1748-1760.
 [http://dx.doi.org/10.1080/22221751.2020.1799723] [PMID:  32691695]

[43]
Ponti, G.; Maccaferri, M.; Ruini, C.; Tomasi, A.; Ozben, T. Biomarkers associated with COVID-19 disease progression. Crit. Rev. Clin. Lab. Sci.,  2020, 57(6), 389-399.
 [http://dx.doi.org/10.1080/10408363.2020.1770685] [PMID:  32503382]

[44]
Malik, P.; Patel, U.; Mehta, D.; Patel, N.; Kelkar, R.; Akrmah, M.; Gabrilove, J.L.; Sacks, H. Biomarkers and outcomes of COVID-19 hospitalisations: systematic review and meta-analysis. BMJ Evid. Based Med.,  2021, 26(3), 107-108.
 [http://dx.doi.org/10.1136/bmjebm-2020-111536] [PMID:  32934000]

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DOI https://dx.doi.org/10.2174/1389203724666230217101202	Print ISSN 1389-2037
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Evaluation of Serum Humanin and MOTS-c Peptide Levels in Patients with COVID-19 and Healthy Subjects

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