Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Aug:224:107825.
doi: 10.1016/j.pharmthera.2021.107825. Epub 2021 Mar 1.

SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: beneficial effects of melatonin

Saeed Mehrzadi  1 , Mohammad Yahya Karimi  1 , Alireza Fatemi  2 , Russel J Reiter  3 , Azam Hosseinzadeh  4
Affiliations
Review

SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: beneficial effects of melatonin

Saeed Mehrzadi et al. Pharmacol Ther. 2021 Aug.

Abstract

Coronaviruses (CoVs) are a group of single stranded RNA viruses, of which some of them such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are associated with deadly worldwide human diseases. Coronavirus disease-2019 (COVID-19), a condition caused by SARS-CoV-2, results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with high mortality in the elderly and in people with underlying comorbidities. Results from several studies suggest that CoVs localize in mitochondria and interact with mitochondrial protein translocation machinery to target their encoded products to mitochondria. Coronaviruses encode a number of proteins; this process is essential for viral replication through inhibiting degradation of viral proteins and host misfolded proteins including those in mitochondria. These viruses seem to maintain their replication by altering mitochondrial dynamics and targeting mitochondrial-associated antiviral signaling (MAVS), allowing them to evade host innate immunity. Coronaviruses infections such as COVID-19 are more severe in aging patients. Since endogenous melatonin levels are often dramatically reduced in the aged and because it is a potent anti-inflammatory agent, melatonin has been proposed to be useful in CoVs infections by altering proteasomal and mitochondrial activities. Melatonin inhibits mitochondrial fission due to its antioxidant and inhibitory effects on cytosolic calcium overload. The collective data suggests that melatonin may mediate mitochondrial adaptations through regulating both mitochondrial dynamics and biogenesis. We propose that melatonin may inhibit SARS-CoV-2-induced cell damage by regulating mitochondrial physiology.

Keywords: Apoptosis; Autophagy; COVID-19; Chaperone proteins; Coronaviruses; Fission; Fusion; Melatonin; Mitochondrial dynamics.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement The authors declare that there are no conflicts of interest.

Figures

Fig. 1
Fig. 1
The employment of chaperone–protease networks by CoVs and the regulatory effects of melatonin. Coronaviruses such as SARS-CoV and SARS-CoV-2 employ mitochondrial protein translocation machinery to inhibit antiviral cellular responses and maintain virus replication. SARS-CoV-2 interacts with Tom complex components. Interaction with may inhibit the interaction of Tom70 with MAVS and induction of antiviral cellular responses (X.-Y. Liu et al., 2010). Polyproteins of SARS-CoV and MERS-CoV have deubiquitinating activity, which influence infected cell ubiquitination. SARS-CoV interacts with proteasome through its nucleocapsid protein to suppress proteolytic activity of proteasomes; this contributes to the inhibition of proteolysis of viral proteins and also suppression of host misfolded protein degradation (J. Lei et al., 2014; Lindner et al., 2005; Q. Wang et al., 2010). Melatonin affects chaperone–protease networks through regulating the expression of HSPs, Tom20 and Tim23, and interacting with UPS machinery, this effects result in the inhibition of aberrant protein accumulation in cells (Bonior et al., 2005; Corpas et al., 2018; Kireev et al., 2014; Martins Branco et al., 2010; S. Mehrzadi, Hemati, et al., 2020; Vriend & Reiter, 2014).
Fig. 2
Fig. 2
Effects of CoVs on mitochondrial dynamics and autophagy as a quality control axis and the regulatory effect of melatonin. Coronaviruses impacts mitochondrial dynamics and mitophagy. Coronaviruses such as SARS-CoV-2 inhibits mitochondrial fusion through suppressing deubiquitination of ubiquitylated forms of Mfn1 and Mfn2 by targeting mitochondrial deubiquitinase (Singh, Chaubey, et al., 2020a). SARS-CoV promotes proteasomal degradation of Drp1 leading to induction of mitophagy (X.-Y. Liu et al., 2010). Some CoVs elevate the ratio of LC3-II/LC3-I leading to the autophagosome accumulation in infected cells (Ko et al., 2017). SARS-CoV-2 targets USP30 protein and inhibits Parkin-mediated mitophagy (Zarandi, Zinatizadeh, Zinatizadeh, Yousefi, & Rezaei, 2021). Difference in the effect of various CoVs on autophagy may result from the fact that autophagy inhibits the replication of some viruses but promotes the replication of other (Guo et al., 2016b). Melatonin regulates mitochondrial dynamics through increasing Mfn2 and OPA1 expression and diminishing Drp1 expression (Ding et al., 2018; Elesela et al., 2020; X. Zhang, Kang, et al., 2020). Melatonin also regulates autophagy/mitophagy pathway (Coto-Montes et al., 2012). In virus infected cells, melatonin shows different effect on autophagy markers including beclin-1, Atg5, Atg12 and Atg16L levels, and LC3-II/LC3-I ratio, dependent on the type of viruses and infection time (Sang et al., 2018; San-Miguel et al., 2014).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acuna-Castroviejo D., Escames G., Rodriguez M.I., Lopez L.C. Melatonin role in the mitochondrial function. Frontiers in Bioscience. 2007;12:947–963. - PubMed
    1. Ahluwalia A., Brzozowska I.M., Hoa N., Jones M.K., Tarnawski A.S. Melatonin signaling in mitochondria extends beyond neurons and neuroprotection: Implications for angiogenesis and cardio/gastroprotection. Proceedings of the National Academy of Sciences of the United States of America. 2018;115:E1942–E1943. - PMC - PubMed
    1. Ahmed E.A. Recommendations for oncological surgical practice in COVID-19 pandemics: A review of literature. Sohag Medical Journal. 2020;24:63–68.
    1. Andersen L.P.H., Gögenur I., Rosenberg J., Reiter R.J. Pharmacokinetics of melatonin: The missing link in clinical efficacy? Clinical Pharmacokinetics. 2016;55:1027–1030. - PubMed
    1. Andersen L.P.H., Gögenur I., Rosenberg J., Reiter R.J. The safety of melatonin in humans. Clinical Drug Investigation. 2016;36:169–175. - PubMed

MeSH terms