Melatonin Protects Mitochondria and ATP Production During SARS-CoV-2 Acute Infection and Post-Infection
Melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous, mitochondria-targeted molecule present in all tested eukarya and bacteria. In March 2022, the first discovery of the serotonin N-acetyltransferase (SNAT) gene — responsible for the penultimate formation of N-acetylserotonin (NAS) before its final conversion into melatonin — in archaea further consolidates the status of melatonin as a regulator of biomolecular condensates in all three domains of life in the cellular empire. RNA viruses including SARS-CoV-2 contain proteins with intrinsically disordered regions that undergo liquid-liquid phase separation (LLPS). LLPS of these proteins form membraneless condensates that act as “viral factories” to facilitate and enhance replication. Phase separation of the SARS-CoV-2 nucleocapsid (N) protein is associated with mitochondrial dysfunction and rewiring of energy production away from oxidative phosphorylation (OXPHOS) to favor aerobic glycolysis in cytoplasm. Increased ATP in cytoplasm supports viral replication. Melatonin protects mitochondria from damage, maintains adequate ATP levels to disassemble “viral factories”, and prevents suppression of host antiviral immune responses by inhibiting nucleocapsid phase separation via antioxidant-dependent and -independent means.
Mitochondria are the “energy powerhouse of the cell” that control respiration and ATP synthesis [ 289, 290], and mitochondria are directly targeted by viruses during infection to facilitate the modulation of cellular metabolism and innate immunity [ 291]. The fundamental features of optimal mitochondrial dynamics are characterized by the ability to connect and elongate (fusion), divide (fission), and turnover (mitophagy). Disruption of mitochondrial bioenergetics during viral infections may explain how RNA viruses hijack mitochondrial dynamics to support viral replication and persistence [ 292]. Both the hepatitis B and hepatitis C viruses promote chronic liver damage by altering the balance of mitochondrial dynamics towards fission and mitophagy in order to reduce virus-induced apoptosis, thereby enhancing viral persistence [ 293, 294]. The SARS-CoV-2 virus relies on a sophisticated, multipronged…