Reviews & Analysis

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.

Eukaryotic transcriptional machinery often shows local enrichment in dynamic clusters at sites of high expression. A study of zebrafish embryos shows that such clusters can fine-tune the timing of zygotic genome activation by sequestering a component required for productive transcription, thus limiting its availability to other genes.

Diverse, specialized immune cells defend against pathogens and cancer cells. A new study reveals the comprehensive lipid compositions of these cells, with unique lipidomes associated with various immune cell types. They show that cell-specific lipid compositions determine a key functional phenotype: their susceptibility to ferroptosis.

Progeria, or premature ageing, is a devastating condition caused by defects in the nuclear envelope and is associated with systemic inflammation. A study now shows in animal models that inhibiting necroptosis, and particularly activity of the RIPK1 kinase, reduces inflammation and results in a meaningful extension in lifespan¹.

β-propeller protein-associated neurodegeneration (BPAN) is caused by loss of functional WIPI4. A new study reports that depletion of WIPI4 induces ferroptosis via changes in mitochondrial membrane lipids, independently of the role of WIPI4 in autophagy, providing insights into the cause of neurodegeneration in BPAN.

Mathiowetz and Olzmann review our current understanding of the mechanisms of lipid droplet biogenesis and turnover, the transfer of lipids and metabolites at membrane contact sites, and the role of lipid droplets in regulating fatty acid flux in lipotoxicity and cell death.

The tumour microenvironment produces nutrients that propel cancer development. New work finds that pancreatic ductal adenocarcinoma cells use one such nutrient, acetate, to alter protein acetylation, rerouting polyamine metabolism and promoting cell growth under acidosis—a finding with potential implications for treating this cancer.

The endoplasmic reticulum (ER) controls the synthesis of lipids and proteins and Ca²⁺ homeostasis, as well as contacting other organelles and the plasma membrane. A study now looks at a process by which this compartment is remodelled in axons during neurogenesis: the lysosomal clearance of ER subdomains, driven by FAM134 and CCPG1 proteins.

In this Perspective, Zhang discusses the latest advances in understanding of iron function, regulation and metabolism, as well as the implications for ferroptosis in health and disease.

Biomolecular condensates are recognized for their ability to compartmentalize the cytoplasm without bounding membranes, but the degree to which they organize the cytoplasm has not been clear. A new study reveals that condensates at a scale of 100 nm are responsible for the organization of at least 18% of the cytoplasmic proteome.

In this Review, Dai, Stockwell, Kroemer, Tang and colleagues offer a comprehensive discussion of the molecular regulation of ferroptosis and highlight how this may be potentially leveraged for therapeutic benefit for disease treatment.

Activation of innate immunity has been linked to the progression of type 1 diabetes. A study now shows that overexpression of METTL3, a writer protein of the m⁶A machinery that modifies mRNA, restrains interferon-stimulated genes when expressed in pancreatic β-cells, identifying it as a promising therapeutic target.

Contractile activity of both the epithelium and underlying mesenchyme are required for epithelial deformation and cell fate acquisition during early mouse hair follicle development. Subsequently, localized basement membrane remodelling facilitates the release of tension-generated pressure to promote cell divisions, tissue fluidification and downgrowth of the developing hair follicle.

The chemoresistant and immunoevasive characteristics of leukaemia stem cells (LSCs) impede the treatment efficacy for acute myeloid leukaemia (AML). We find that inhibiting the tyrosine phosphatase SHP-1 effectively alters the metabolic state of LSCs, making them more susceptible to chemotherapy and immune surveillance in AML.

Mechanical forces are ubiquitously present in biology. In recent years, it has become clear how plasma membranes detect these forces — but how do intracellular organelles such as lysosomes do the same, and what might be the functions of such intracellular mechanosensing? Answers may come through a report of a lysosomal mechanosensitive ion channel, TMEM63.

As a major microenvironmental component in B cell lymphomas, T cells are highly relevant for current immunotherapeutic treatment strategies of such tumours. A study now provides an unprecedented multimodal insight into the composition and features of T cell subsets of the four main types of nodal B cell non-Hodgkin lymphoma.

The generation of clathrin-coated vesicles during endocytosis requires the co-ordinated recruitment of dozens of proteins to the plasma membrane. We discovered that the plant TPLATE (or TSET) complex (TPC) undergoes biomolecular condensation through interactions with plasma membrane phospholipids and, via weak multivalent interactions, recruits clathrin and other endocytic proteins to facilitate the efficient progression of endocytosis.