Reviews & Analysis

Mutations in the gene encoding the E3 ubiquitin ligase TRIAD3A cause adult-onset neurodegenerative disorders. We reveal that the ubiquitin ligase activity of TRIAD3A promotes its liquid–liquid phase separation. TRIAD3A co-partitions with tau into droplets, where tau forms fibrillar aggregates. TRIAD3A mediates the degradation of these aggregates through its role as an autophagy adaptor.

The role of RNA in preserving the integrity and dynamics of membrane-bound organelles remains largely unexplored. A study now identifies the Golgi-resident protein GM130 as an RNA-binding protein that scaffolds the Golgi ribbon in a polyadenylated-RNA-dependent manner.

Transcription factors (TFs) and cis-regulatory elements (CREs) drive organism development. Suboptimal binding of TFs to CREs is shown to be key for the specificity of gene expression. New work now indicates that a similar principle governs the activities of TFs and their regulatory specificity.

Cellular organelles form an interconnected and dynamic network that orchestrates cellular functions. Using a multispectral imaging and computational analysis approach (‘OrgaPlexing’), a study now identifies multi-organelle units as crucial regulators of metabolic reprogramming in primary macrophages upon inflammatory stimuli.

The subcellular localization of numerous mRNAs has been demonstrated. This Review presents the different means of mRNA localization described and discusses how they can account for the widespread occurrence of this phenomenon.

R-loops and G-quadruplexes are non-canonical nucleic acid structures with known roles in genome organization. Here, Wulfridge and Sarma highlight emerging roles in DNA repair and transcriptional and epigenetic gene regulation.

Several processes of regulated cell death engage or use mitochondria, which are thus central hubs that not only coordinate cell death but also elicit non-lethal signalling mediated by mitochondrial outer membrane permeabilization.

Ferroptosis is a form of cell death that is characterized by morphological abnormalities of mitochondria and the overwhelming peroxidation of phospholipids. Certain tumours are susceptible to ferroptosis, which could be exploited to treat cancers.

Aminoacyl-tRNA synthetases can promote or suppress cancer progression by regulating codon-dependent translation. A study now shows that valine aminoacyl-tRNA synthetase (VARS) promotes therapeutic resistance of melanoma to MAPK pathway inhibitors by enhancing translation of valine-enriched genes, including the fatty acid oxidation gene HADH.

Oocyte development involves the prolonged and intricate process of building a distinctive transcriptome and epigenome to anticipate embryogenesis after fertilization. Research now shows that mouse oocytes use an unusual chromatin signature to mark regulatory elements, and that the transcription factors TCF3 and TCF12 have a key role.

Sensing stress within the endoplasmic reticulum (ER), the ER transmembrane protein IRE1α initiates a signal transduction pathway to restore homeostasis. A study finds that this process requires an ER membrane-bound phase separation event that leads to the local assembly of stress granules (SGs) and delivery of signalling components.

Mitochondrial damage in stress conditions results in the release of mitochondrial DNA (mtDNA), causing inflammation that is linked to various diseases. We discovered a mechanism for the elimination of this harmful mtDNA — ‘nucleoid-phagy’. Targeting this process represents another way to treat mitochondrial damage-related diseases.

Biological clocks can be used to evaluate the age of a cell or organisms. This Perspective proposes the concept of an intrinsically disordered protein (IDP) clock, whereby the aggregation state of an IDP encodes for a biological ageing signature.

Granath-Panelo and Kajimura review emerging evidence of mitochondrial heterogeneity in different contexts and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

Two new landmark studies use innovative and complementary lineage tracing approaches in human cerebral organoids to reveal symmetric stem cell division and direct neurogenesis of basal radial glial cells to enable cortical growth, expansion and differentiation.

Metastatic colonization involves cancer-cell-intrinsic mechanisms and microenvironmental interactions, and a better understanding of the factors that influence the final, post-extravasation phases is crucial for therapeutically targeting metatstasis.

We show that the mitochondrial fission proteins MiD49 and MiD51 are activated by fatty acyl-coenzyme A (FA-CoA). FA-CoA binds in a previously identified pocket located within MiDs, inducing their oligomerization and ability to activate the dynamin DRP1, ultimately promoting mitochondrial fission. Activated MiDs synergize with mitochondrial fission factor (MFF) in stimulating DRP1 activity, leading us to hypothesize that MiDs act upstream of MFF during mitochondrial fission.

Our understanding of the basic mechanisms of autophagy is growing, but many questions remain about the types of autophagy cells use, when they use them, and how they function in different contexts. We asked emerging and established leaders in the field to discuss the questions and areas that they are most excited about to deepen our understanding of autophagy.

When transcription by RNA polymerase II is stalled by ultraviolet-induced DNA damage, it recruits repair factors, leading to excision of the damaged site and DNA synthesis to fill the gap. Three new studies show that, for aldehyde-induced DNA crosslinks, repair is activated by the same factors, but without base excision and gap filling.

Organ morphogenesis begins with proliferation, which results in tissue pressures and site-specific YAP expression, nuclear translocation and signalling. A study now reports the involvement of anisotropy, localized pressure and YAP signalling in organizer-forming cascades, introducing a new chapter of molecular mechanobiology of organogenesis.