Volume 25 Issue 7, July 2023

The PHD–pVHL pathway is essential for oxygen-dependent prolyl hydroxylation of HIFA. A recent study identifies RIPK1 as a hydroxylation target in this pathway during hypoxia-induced cell death and presents a 2.8 Å resolution crystal structure of the pVHL–elongin B/C complex bound to hydroxylated RIPK1.

Disruptions in the autophagy–lysosome pathway in neurons have been implicated in Alzheimer’s disease. A study now reports that autophagy is also critical for disease-associated microglia surrounding amyloid plaques and is protective against microglial senescence and neuropathology in an Alzheimer’s disease mouse model.

Mitochondria are dynamic organelles, changing their morphology and functional capacity in response to physiological and metabolic cues. A study uncovers a role for the typically nutrient-responsive mTORC2 during fasting in vivo to promote mitochondrial fission via the activation of a signalling pathway that involves NDRG1 and CDC42.

The nuclear envelope participates in the spatial regulation of DNA repair, but the mechanisms behind this are unclear. A study now reports that a nuclear envelope-localized nuclease, NUMEN/ENDOD1, guides the choice of DNA-repair pathway by inhibiting the resection of DNA ends and aberrant recombination, ensuring genome stability.

The compact state of chromatin induced by the methylation of lysine 9 on histone H3 has long been implicated in a heritable state of transcriptional repression. A study now shows that transient deposition of H3K9me3 helps to stabilize stalled DNA replication forks, while its reversal enables accurate fork restart.

Class 3 phosphatidylinositol-3-kinase (PI3K) has a surprising nuclear function as a coactivator of the circadian clock Bmal1–Clock transcription factor complex for rhythmic purine nucleotide metabolism. This finding opens new avenues for establishing the roles of nuclear subunits of class 3 PI3K in metabolic homeostasis.

The rabbit is an important model species for developmental and translational research. Here, we used histological imaging and single-cell transcriptomics to characterize gastrulation and early organogenesis in the rabbit. We identified substantial transcriptional differences between the rabbit and mouse, highlighting the power of cross-species comparative genomics to elucidate early human development.

Zhou et al. describe an intracellular transport pathway of low-density lipoprotein (LDL)–LDL receptor from the plasma membrane that bypasses lysosomes and delivers cholesterol to mitochondria for steroidogenesis.

Zhang, Xu, Liu, Wang et al. identify an inhibitory mechanism for RIPK1 kinase through EGLN1/pVHL-mediated proline hydroxylation, which is disrupted upon prolonged hypoxia that activates RIPK1 activity to promote cell death and inflammation.

Choi et al. show that autophagy is activated in disease-associated microglia in Alzheimer’s disease mouse models, which prevents microglial senescence entry. Blocking microglial autophagy aggravates neuropathology in Alzheimer’s disease mice.

Alkhoury et al. show that the class 3 phosphatidylinositol-3-kinase Vps15 subunit coactivates the circadian clock transcription factor Bmal1–Clock for metabolic rhythmicity in the liver and promotes pro-anabolic de novo purine synthesis.

Martinez-Lopez et al. show that fasting or lipid availability stimulates mTORC2 activity in the liver, leading to phosphorylation of NDRG1 and NDRG1–CDC42-mediated mitochondrial fission.

Through a genome-wide CRISPR synthetic viability screen for PARP-inhibitor resistance, Chen and Ge et al. show that transmembrane nuclease NUMEN directs double-stranded DNA break repair pathway choice at the nuclear periphery.

Gaggioli, Lo et al. show that the histone methyltransferase EHMT2/G9a catalyses heterochromatin assembly at stressed replication forks. Untimely heterochromatin disassembly by demethylase KDM3A exposes forks to PRIMPOL-mediated genome instability.

Han et al. identify the long non-coding RNA LIPTER as a key mediator of lipid droplet transport and metabolism in human cardiomyocytes. LIPTER overexpression mitigates cardiomyopathy and preserves cardiac function in obese and diabetic mouse models.

Gao, Mathur, Tam and colleagues characterize transcriptomic and epigenomic alterations at the maternal–fetal interface in patients with COVID-19, thereby providing insights into aberrant pregnancy outcomes associated with SARS-COV-2 infection.

Ton, Keitley et al. provide a morphological and molecular atlas of rabbit development. Comparative studies reveal that combining rabbit and mouse atlases can serve as a model for dissecting early primate development.