Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders.

Russel J. Reiter,Doris Loh

doi:10.3390/antiox10091483

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.

Highlights

Present in all cells, biomolecular condensates are membraneless organelles (MLOs) containing proteins, ribonucleic acids (RNAs), and other nucleic acids [1]
The rapid translocation of mitochondrial Adenosine triphosphate (ATP) synthase to lipid rafts may be integral to these adaptive responses because ATP functions as a biological hydrotrope [30,178], increasing the solubility of positively charged, intrinsically disordered proteins [179], but may act as a universal and specific regulator of intrinsically disordered regions (IDRs) capable of altering physicochemical properties, conformation dynamics, assembly, and aggregation [45], in addition to providing phosphates as an energy source to fuel post-translational modifications that regulate the fluctuation of biomolecule phase separation during condensate formation [79,178]
Eukaryotes and prokaryotes use ATPases localized in cell membranes and lipid raft domains to produce and release ATP energy [122,127,136,152]; increased ATPase activities from enhanced membrane fluidity [357,358] can impact how ATP interacts with phospholipids in bilayers [216] and modulate the liquid–liquid phase separation (LLPS) of MLOs formed at membrane surfaces [45]

Summary

Introduction

Biomolecular condensates are membraneless organelles (MLOs) containing proteins, ribonucleic acids (RNAs), and other nucleic acids [1]. These micronscale macromolecules that can assemble into liquid-like droplets have been proposed to be the origin of life [2]. The change in free energy of −7.3 kcal/mol associated with this chemical reaction is used by cells to perform energetically favorable reactions [15], including relevant post-translational modification (PTM) such as phosphorylation [16], ubiquitination [17,18], and SUMOylation that may regulate condensate nucleation, composition, and growth [19,20]. The timely dissolution of pathological amyloid fibrils may be dependent on cellular levels of ATP, which has recently been identified as a biological hydrotrope [30]—an amphiphilic molecule that may behave as a surfactant [31] which can reduce tension between solute and solvent, and increase solubility in an energy-independent manner

ATP Regulates Biomolecular Condensates

The Interdependence between Membranes and Membraneless Organelles

Lipid Rafts and Biomolecular Condensates in Health and Disease

Melatonin May Regulate Glycolytic G Bodies by Increasing ATP

Potential Regulation of RNA and RNA m6A Modifications by Melatonin

Findings

Conclusions