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Cell competition is a highly conserved mechanism through which cells with lower fitness levels than surrounding cells are actively removed from tissues. Differences in fitness may result from intrinsic tissue heterogeneity or be caused by differentiation, infections, or mutations. The resulting competition dynamics act as a key regulator of various biological processes during development and homeostasis. The underlying mechanical factors often remain unclear. Here, we discuss the biophysical principles of cell competition and elimination via extrusion or delamination. Recent advances have uncovered how fitness is determined by cellular mechanical properties, which can regulate winning or losing, and how cells use forces to outcompete each other. Furthermore, forces can influence the fate and direction of eliminated loser cells, which govern functional tissue development and disease progression.

Neuronal size varies across evolution, diseases, and brain regions. It has long been regarded as a descriptor, not a driver of function. Using triploid Xenopus, Liu et al. show that neuronal enlargement remodels neurite geometry, reduces proliferation, increases phospho-extracellular signal regulated kinase (pERK) responses, and alters behavior, linking cellular scaling to brain function.

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The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.

Telomere crisis contributes to cancer genome evolution. Beyond the loss of end protection, replication defects at short telomeres give rise to aberrant fork intermediates that can be resolved by microhomology-mediated end joining. Such mutagenic repair yields chromosomal fusions and complex rearrangements that shape cancer genomes.

Alternative lengthening of telomeres (ALT) is a recombination-mediated telomere maintenance mechanism. Although the core ALT machinery is defined, the initiating events remain unresolved. Taylor et al. demonstrate that telomeric heterochromatin enrichment drives nuclear compartmentalization, promyelocytic leukemia body nucleation, and telomere clustering, establishing a chromatin-defined environment that is permissive for recombination.

Neural stem cells (NSCs) span a continuum of cellular states that share fundamental properties with their differentiated glial progeny. Recent single-cell studies have refined our understanding of the diversity within both NSC and glial populations, revealing a highly dynamic and interconnected landscape of cell identities. In this review, we examine the glial nature of NSCs, emphasizing their heterogeneity and the stem- and progenitor-like properties shared with the differentiated glia. We focus particularly on astrocytes and integrate evidence from invertebrate models demonstrating that glial cells possess an intrinsic capacity for neurogenesis. Together, these findings highlight areas of convergence between astrocyte plasticity and NSC-associated properties, with important implications for nervous system regeneration and brain cancer.

Errors in transcription and RNA processing generate aberrant transcripts that can produce truncated, nonfunctional, or dominant-negative proteins. RNA surveillance pathways, centered on the RNA exosome, recognize diverse processing defects and initiate targeted RNA degradation. These mechanisms also regulate the short half-life of chromatin-associated noncoding RNAs through co- and/or post-transcriptional degradation. This review examines how the RNA exosome achieves substrate specificity, focusing on its interactions with the helicase cofactors mRNA transport 4 (MTR4) and superkiller 2 (SKIV2L) and the modulatory role of RNA modifications such as N6-methyladenosine. The broad spectrum of RNA exosome targets underscores its central functions in transcription, translation, genome integrity, and cell fate determination.

Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed ‘Mitochondrial Safeguard (MitoSafe)’, in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.

Endoplasmic reticulum (ER)-resident ubiquitin ligases are essential to cellular homeostasis and diverse signaling pathways, functioning in protein quality control, lipid metabolism, innate immunity, and interorganelle communication. While best known for their roles in ER-associated degradation (ERAD) of misfolded proteins, accumulating evidence shows that they also mediate the regulated turnover of functional ER proteins and contribute to ER-phagy, thereby expanding their roles in ER homeostasis. This review summarizes recent advances in understanding substrate recognition mechanisms employed by ER ubiquitin ligases and how these enzymes coordinate ERAD and ER-phagy, with a primary focus on mammalian systems. We further discuss their roles in ER homeostasis and immune responses, and how their dysregulation contributes to diseases such as neurodegeneration and immune disorders.

Co-directional (CD) transcription–replication conflicts (TRCs) arise when the DNA replication and transcription machineries progress along the same DNA template. Although generally considered less severe than head-on (HO) TRCs, CD TRCs are now recognized as frequent and actively regulated events that influence genome stability. The Cullin 3–Potassium channel tetramerization domain containing 10 (KCTD10) ubiquitin ligase complex functions as a bivalent sensor that detects CD collisions and directs the nonproteolytic ubiquitination of the elongation factor TCEA2, transiently remodeling RNA polymerase II to permit replisome bypass. This sensing-driven remodeling reframes CD TRCs as dynamic decision nodes where replication and transcription priorities are continuously negotiated, highlighting how conflict geometry, ubiquitin signaling, and genome maintenance are functionally integrated.