Pub Date : 2026-01-15DOI: 10.1038/s41556-025-01861-0
Melina Casadio
{"title":"Mitoxyperilysis as a distinct cell death type","authors":"Melina Casadio","doi":"10.1038/s41556-025-01861-0","DOIUrl":"10.1038/s41556-025-01861-0","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"1-1"},"PeriodicalIF":19.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145970253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41556-025-01854-z
Siddharthan B. Thendral, Sasha Bacot, Ian T. Ryde, Katherine S. Morton, Qiuyi Chi, Isabel W. Kenny-Ganzert, Joel N. Meyer, David R. Sherwood
The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity. Thendral et al. describe a mitophagic programme that removes deleterious mtDNA during the oocyte-to-zygote transition in Caenorhabditis elegans, promoting mitochondrial health and offspring survival. Loss of this mitophagy leads to mutant mtDNA accumulation.
{"title":"Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance","authors":"Siddharthan B. Thendral, Sasha Bacot, Ian T. Ryde, Katherine S. Morton, Qiuyi Chi, Isabel W. Kenny-Ganzert, Joel N. Meyer, David R. Sherwood","doi":"10.1038/s41556-025-01854-z","DOIUrl":"10.1038/s41556-025-01854-z","url":null,"abstract":"The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity. Thendral et al. describe a mitophagic programme that removes deleterious mtDNA during the oocyte-to-zygote transition in Caenorhabditis elegans, promoting mitochondrial health and offspring survival. Loss of this mitophagy leads to mutant mtDNA accumulation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"268-284"},"PeriodicalIF":19.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1038/s41556-025-01852-1
Tyler H. Stanage, Shudong Li, Sandra Segura-Bayona, Aurora I. Idilli, Rhona Millar, Graeme Hewitt, Simon J. Boulton
SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase–polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1–WDR48 deubiquitinase complex as a positive modulator of SLFN11 activation in PrimPol-deficient cells, revealing an addiction to the Fanconi anaemia pathway to resolve cisplatin lesions. Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress. Stanage et al. identify a role for transfer RNA nuclease SLFN11 in replication-stress-induced cell death in cisplatin-treated cells lacking PrimPol. SLFN11 is activated upon single-stranded DNA accumulation at stalled forks followed by replication protein A exhaustion and cell death.
{"title":"RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress","authors":"Tyler H. Stanage, Shudong Li, Sandra Segura-Bayona, Aurora I. Idilli, Rhona Millar, Graeme Hewitt, Simon J. Boulton","doi":"10.1038/s41556-025-01852-1","DOIUrl":"10.1038/s41556-025-01852-1","url":null,"abstract":"SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase–polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1–WDR48 deubiquitinase complex as a positive modulator of SLFN11 activation in PrimPol-deficient cells, revealing an addiction to the Fanconi anaemia pathway to resolve cisplatin lesions. Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress. Stanage et al. identify a role for transfer RNA nuclease SLFN11 in replication-stress-induced cell death in cisplatin-treated cells lacking PrimPol. SLFN11 is activated upon single-stranded DNA accumulation at stalled forks followed by replication protein A exhaustion and cell death.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"240-254"},"PeriodicalIF":19.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01852-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s41556-025-01842-3
He Ren, Leina Ma, Xiaoming Jiang, Zhimin Lu
Lactate acts as a metabolic fuel, a signalling molecule and a protein modifier. A study reveals that in glioblastoma, a lactate-mediated metabolic crosstalk between tumour-associated macrophages and glioblastoma stem-like cells enhances DNA repair, promotes stemness, drives immune evasion and accelerates tumour growth.
{"title":"Immune evasion by macrophage-derived lactate","authors":"He Ren, Leina Ma, Xiaoming Jiang, Zhimin Lu","doi":"10.1038/s41556-025-01842-3","DOIUrl":"10.1038/s41556-025-01842-3","url":null,"abstract":"Lactate acts as a metabolic fuel, a signalling molecule and a protein modifier. A study reveals that in glioblastoma, a lactate-mediated metabolic crosstalk between tumour-associated macrophages and glioblastoma stem-like cells enhances DNA repair, promotes stemness, drives immune evasion and accelerates tumour growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"220-221"},"PeriodicalIF":19.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s41556-025-01848-x
We present SpaHDmap, a deep learning framework that integrates histology images with spatial transcriptomic data to derive high-resolution and interpretable spatial metagenes. We demonstrate that SpaHDmap effectively generates fine-grained spatial metagenes, reveals refined spatial structures and enables joint analysis of multiple samples across different experimental conditions.
{"title":"Revealing high-resolution spatial metagenes from spatial transcriptomics","authors":"","doi":"10.1038/s41556-025-01848-x","DOIUrl":"10.1038/s41556-025-01848-x","url":null,"abstract":"We present SpaHDmap, a deep learning framework that integrates histology images with spatial transcriptomic data to derive high-resolution and interpretable spatial metagenes. We demonstrate that SpaHDmap effectively generates fine-grained spatial metagenes, reveals refined spatial structures and enables joint analysis of multiple samples across different experimental conditions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"224-225"},"PeriodicalIF":19.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41556-025-01844-1
Ruben van der Lugt, Jacqueline J. L. Jacobs
Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signature and molecular behaviour of human telomeric chromatin. Recent structural and genetic studies further highlight the distinctive and dynamic nature of the telomeric architecture. Here we present an updated perspective on telomeric chromatin, focusing on the unique features that set telomeres apart from other genomic regions and that equip them to address the specific challenges at chromosome ends. In addition, we discuss how alterations in telomeric chromatin influence stem cells, inherited diseases and cancer, demonstrating how telomere architecture governs both its integrity and function. This Review presents an updated view on telomeric chromatin as a dynamic structure with a specialized histone organization and discusses the mechanisms of its regulation by cis-acting subtelomeric elements, as well as their relevance in disease.
{"title":"Structural organization and function of telomeric chromatin","authors":"Ruben van der Lugt, Jacqueline J. L. Jacobs","doi":"10.1038/s41556-025-01844-1","DOIUrl":"10.1038/s41556-025-01844-1","url":null,"abstract":"Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signature and molecular behaviour of human telomeric chromatin. Recent structural and genetic studies further highlight the distinctive and dynamic nature of the telomeric architecture. Here we present an updated perspective on telomeric chromatin, focusing on the unique features that set telomeres apart from other genomic regions and that equip them to address the specific challenges at chromosome ends. In addition, we discuss how alterations in telomeric chromatin influence stem cells, inherited diseases and cancer, demonstrating how telomere architecture governs both its integrity and function. This Review presents an updated view on telomeric chromatin as a dynamic structure with a specialized histone organization and discusses the mechanisms of its regulation by cis-acting subtelomeric elements, as well as their relevance in disease.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"226-239"},"PeriodicalIF":19.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1038/s41556-025-01853-0
Jossie J. Yashinskie, Xianbing Zhu, Grace H. McGregor, Karl A. Wessendorf-Rodriguez, Katrina Paras, Julia S. Brunner, Benjamin T. Jackson, Abigail Xie, Richard Koche, Christian M. Metallo, Lydia W. S. Finley
Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR–Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability. Yashinskie, Zhu and colleagues show that p53 activation triggers increased synthesis and accumulation of phospholipids, with enhanced activation of autophagy and lysosomal catabolism programmes and increased reliance on lipid headgroup recycling.
{"title":"p53 increases phospholipid headgroup scavenging in senescence","authors":"Jossie J. Yashinskie, Xianbing Zhu, Grace H. McGregor, Karl A. Wessendorf-Rodriguez, Katrina Paras, Julia S. Brunner, Benjamin T. Jackson, Abigail Xie, Richard Koche, Christian M. Metallo, Lydia W. S. Finley","doi":"10.1038/s41556-025-01853-0","DOIUrl":"10.1038/s41556-025-01853-0","url":null,"abstract":"Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR–Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability. Yashinskie, Zhu and colleagues show that p53 activation triggers increased synthesis and accumulation of phospholipids, with enhanced activation of autophagy and lysosomal catabolism programmes and increased reliance on lipid headgroup recycling.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"296-306"},"PeriodicalIF":19.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01853-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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