Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Abstract

Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…Conversely, the level of CD4+ T cells—regarded as a biomarker of protective immunity [ 285 ]—is usually significantly reduced in adults with severe or critical COVID-19 compared to healthy controls [ 286 ]. Melatonin protects both mitochondrial and extracellular ATP production by maintaining curvature and ensuring structural integrity of lipid domains where ATP synthases and ATPases are located [ 287 ]. The ability of SARS-CoV-2 to disrupt ATP synthases, and its efficacy in modulating mitochondrial dynamics and metabolism to evade host immune response, enhance replication, and establish viral persistence may be attenuated by the well-timed presence and/or application of adequate melatonin [ 288 ].…”

Identification of the function and mechanism of m6A reader IGF2BP2 in Alzheimer’s disease

“…In previous studies, pathway analyses have predicted the potential effect of m6A methylation RNA in AD, and the high-throughput sequencing of m6A RNA methylation alterations in AD and C57BL/6 mice was also verified this association [ 52 , 53 ]. Besides, m6A controls key gene expression in AD- related pathways, which indicates that m6A renders its essential roles in aging and neurodegenerative diseases [ 54 ]. In our study, we found that IGF2BP2, as a m6A reader, increased in AD patients than in normal people, which might indicate a potential relationship with the occurrence of AD.…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…In addition, under physiological conditions, Cu 2+ bound to full-length, uncleaved PrP can induce misfolding that increases seeding, which serves as templates for aggregation [ 300 , 301 ]. Melatonin is not only a potent antioxidant capable of chelating copper and modulating ROS-dependent prion cleavage, but is also proposed to be an important regulator of phase separation [ 125 ].…”

“…Melatonin may efficiently mediate important PTMs that regulate proteins which can form physiological condensates or pathological prion-like aggregates due to its ability to protect mitochondrial and cytoplasmic ATP levels and maintain requisite RNA concentration, which not only ensure proper formation and dissolution of condensates [ 125 ] but possibly also modulate reentrant phase transitions that are important biochemical timekeeping RNA-dependent transformations where increased RNA dissolves condensates to return to an identical or macroscopically similar state before the phase transition [ 324 ]. Since prion targeting of lipid rafts [ 272 , 325 , 326 ] can affect membrane signaling [ 327 , 328 ] and lipid composition [ 329 ], the role of melatonin in the prevention of lipid peroxidation, modification of lipid hydrocarbon chain to promote phase separation in ternary membrane models [ 330 , 331 ], stabilizing lipid liquid ordered (L o ) to liquid disordered (L d ) phase separation over a range of temperatures [ 332 ], and displacing cholesterol in competitive binding to lipid molecules [ 330 ] provides additional insight into the complex relationship between melatonin and prion physiological and potential pathological conversion mediated by phase separation and associated processes.…”

“…The conversion of PrP C into self-templating aggregates is now believed to be associated with liquid–liquid phase separation (LLPS), which is an energy-efficient thermodynamic process that results in the rapid formation and dissolution of biomolecular condensates used by living organisms as adaptation to changing environments [ 120 , 121 , 122 , 123 , 124 ]. Living organisms may have always relied upon melatonin to effectively modulate prion propagation using unique features including the regulation of liquid–liquid phase separation [ 125 ].…”