Reviews & Analysis

Ancestral experience of mitochondrial stress is now found to render progeny of the roundworm Caenorhabditis elegans more resistant to the same insult for up to four generations. A DNA modification, N6-methyldeoxyadenine, is implicated in the inheritance of this stress adaptation.

RIPK1 plays a key role in several inflammatory and cell death signalling pathways. Understanding its regulation is pivotal for identifying diseases that might therapeutically benefit from RIPK1 inhibition. Recent studies now show that TBK1 and IKKε constitute a cell death checkpoint that restrains RIPK1 activation.

BAF is a heterogenous chromatin-remodelling complex, frequently mutated in cancer. A study now defines genome-wide localization patterns of three complexes, cBAF, PBAF and previously unknown ncBAF, and reveals the ncBAF complex as a specific vulnerability in synovial sarcoma and malignant rhabdoid tumours.

Lawson et al. review recent advances in single-cell technologies and discuss in detail how they can be leveraged to understand tumour heterogeneity and metastasis.

In this Review, Leidal et al. discuss the role and regulation of autophagy in aging. They cover how autophagy promotes longevity and restricts cellular damage, and discuss autophagy modulators for the potential treatment of age-related diseases.

During mitosis, the kinetochore connects chromosomes to spindle microtubules and enables chromosome segregation. A genetic study in vertebrate cells demonstrates phosphorylation-regulated plasticity of kinetochore assembly and highlights the role of the centromere protein T in load-bearing kinetochore–microtubule attachment.

Newly synthesised lysosomal proteins are sorted from other cargo on the secretory pathway for delivery to endolysosomal compartments. A study now shows that the Batten disease protein, CLN8, acts as a recycling receptor to sort soluble lysosomal enzymes for export from the endoplasmic reticulum to the Golgi.

Goddard et al review recent advances in our understanding of dormant tumour cells, highlight their cross-talk with immune responses, and elaborate therapeutic implications to treat metastatic malignancies.

Classical actin-dependent, integrin-mediated cell–matrix adhesions disassemble before mitotic rounding. Yet, to transmit positional information and facilitate daughter-cell separation, dividing cells maintain connections to the matrix. A previously unidentified class of actin-independent integrin adhesions may fulfil this task.

β-catenin regulates cell–cell adhesion and maintains stemness through Wnt signalling, but how these functions are mechanistically related is not fully understood. A study now identifies CRAD as the mechanistic link, providing insight into how dysregulation of epithelial adhesion contributes to Wnt-driven tumorigenesis.

The cancer-suppressive mechanisms underlying a tissue’s response to spontaneous oncogenic mutations during homeostasis are largely unknown. A study now explores how clonal expansion of epidermal stem cells with specific oncogenic mutations might be restricted by their elimination through enforced differentiation.

Functional genetic screening of mice and other mammals is exceedingly challenging. A CRISPR-based mutagenesis screen in mice has successfully revealed amino acids vital for protein function of the DND1 gene, missense mutations of which lead to defects in primordial germ cell development.

The intestinal crypt has become the prototype compartment to investigate adult stem cell biology, and the list of identified intestinal stem cell (ISC) markers is already extensive. A comprehensive study now uncovers an additional layer in ISC regulation by introducing long noncoding RNA lncGata6 to the stem cell repertoire.

Intra-tumour heterogeneity manifests both at the level of mutational burden, and at a functional level within genetically homogenous populations. A new modelling approach suggests stemness within colorectal tumours is defined by microenvironmental cues secreted from cancer-associated fibroblasts rather than cell-intrinsic properties.

Paraspeckles are nuclear bodies built on the long noncoding RNA, NEAT1, that regulate cellular homeostasis, but how they sense and help under stress is unclear. A study now shows mitochondrial stress modulates paraspeckles by altering NEAT1 expression with a feedback loop that influences mitochondrial homeostasis.

Ferroptosis is a regulated non-apoptotic form of cell death and its functional role in tumorigenesis remains elusive. A study now shows that the tumour suppressor BAP1 enhances ferroptosis by modulating expression of the cystine transporter SLC7A11, leading to improved control of tumour growth.

In this Review, Doherty and Baehrecke discuss the multiple roles of autophagy during cell survival and cell death. They cover the interplay between autophagy, apoptosis and necrosis, as well as engulfment and inflammation.

Maintaining plasma membrane tension is important for eukaryotic cells. How altered membrane tension is sensed and relayed to downstream factors, such as the target of rapamyin complex 2 (TORC2), is poorly understood. Reorganization of a signalling lipid into discrete membrane domains is now shown to inactivate TORC2 in yeast.

Rag GTPases facilitate mTORC1 activation by recruiting it to Rheb at the lysosome when amino acids are abundant. A study now shows that the amino acid-induced change in the GTP/GDP-binding state of the Rag heterodimer paradoxically increases its dynamic release from the Ragulator at the lysosome and may limit mTORC1 activation.

In this Review, Tavernarakis and colleagues describe recent advances in delineating the molecular mechanisms that mediate mitophagy, and discuss the complex roles of this pathway in physiological and pathological contexts.