Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications

Abstract

Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions.

Fig. 1

The localization of membraneless organelles. The cells contain membrane-bound organelles as well as MLOs such as Nucleolus, P granules, Paraspeckles, Stress Granules, Processing Bodies, Cajal Bodies, and Nuclear Speckles. Condensates associated with membranes include T-cell receptor, stress granules associated with lysosomes, and biomolecular condensates within the Golgi apparatus

Fig. 2

Multivalent interactions involved in phase separation. a Protein-protein interactions. b Protein-RNA interactions. c RNA-RNA interactions. d Multivalent interactions between IDRs include charge-charge interaction, hydrogen bond, Dipole-Dipole interaction, π–π stacking, and cation–π interaction

Fig. 3

Molecular composition of various MLOs. a Nucleolus contains RBP: RNA-binding proteins (RBP), ribosomal RNA and proteins (rRNA and r-proteins). b SGs contain RBP, mRNA, ribosomal subunits, eIFs. c P-Bodies contain mRNA, decapping enzymes, RBP, exonucleases. d Cajal Bodies contain small nuclear RNAs (snRNAs), splicing factors and p80/coilin. e Germ Granules RNAs, RBPs, and translational regulators. f Nuclear Speckles contain pre-mRNA splicing factors, RNA polymerase II, and transcriptional regulators

Fig. 4

Biological functions of MLOs. The biological functions of MLOs include gene expression, mRNA processing, translation, cellular stress responses, and signal transduction

Fig. 5

The role of MLOs in cardiovascular diseases. a Within the nucleus, VGLL3 undergoes LLPS facilitated by its LCD, forming condensates alongside the EWSR1, which inhibits miR-29, leading to increased collagen production and cardiac fibrosis. b The mutated RBM20 from nuclear splicing speckles relocates to SG, leading to dilated cardiomyopathy

Fig. 6

Diseases linked to dysregulation of MLOs. Abnormal phase separation or dysfunction of specific biomolecular condensates can disrupt cellular homeostasis and contribute to a range of diseases, including neurodegenerative diseases, cancer, hematological diseases, aging and metabolism disorder

Fig. 7

Regulation of MLOs through modifications occurring after translation. The formation and function of MLOs are regulated by modifications occurring after translation, including phosphorylation, acetylation, methylation, and PARylation