Pub Date : 2026-01-23DOI: 10.1038/s41556-025-01858-9
Ali Can Savas, Sergei I Grivennikov
{"title":"Metabolic borders shape immune resistance.","authors":"Ali Can Savas, Sergei I Grivennikov","doi":"10.1038/s41556-025-01858-9","DOIUrl":"https://doi.org/10.1038/s41556-025-01858-9","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":" ","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041423","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}
Lysosomes maintain a highly acidic lumen to regulate H+-dependent hydrolase-mediated degradation, but how protons are ‘leaked’ out to regulate organellar functions through cytosolic effectors remains unknown. Here we developed DNA nanodevices on the cytosolic leaflet of lysosomal membranes to monitor juxta-organellar pH in cells. Unexpectedly, we revealed a radiating acidic layer (up to 21 nm in thickness) on the outer surface of all lysosomes, typically 0.2–0.7 pH units more acidic than the neutral cytosol. This acidic nanolayer is established and maintained primarily by TMEM175, a lysosomal H+ efflux channel associated with Parkinson’s disease. Activation of TMEM175 causes opposite pH changes on both sides of lysosomes; however, it is the juxta-lysosomal, not the luminal, acidity that determines lysosome positioning in cells with dynein adaptor RILP acting as a juxta-lysosomal pH sensor. Hence, through inside-out proton conduits, lysosomes create a steady acidic surrounding that acts as a nano-interface for cytosolic machineries to regulate organellar activities.
{"title":"DNA nanodevices detect an acidic nanolayer on the lysosomal surface","authors":"Yutong Zhang, Meiqin Hu, Yaping Meng, Xin Wang, Fangqian Huang, Ping Li, Yuting Zhuo, Danzhen Chen, Zhimin Wang, Qiang Zhang, Hui Wu, Yao He, Yulin Du, Haoxing Xu, Liping Qiu, Weihong Tan","doi":"10.1038/s41556-025-01855-y","DOIUrl":"https://doi.org/10.1038/s41556-025-01855-y","url":null,"abstract":"Lysosomes maintain a highly acidic lumen to regulate H+-dependent hydrolase-mediated degradation, but how protons are ‘leaked’ out to regulate organellar functions through cytosolic effectors remains unknown. Here we developed DNA nanodevices on the cytosolic leaflet of lysosomal membranes to monitor juxta-organellar pH in cells. Unexpectedly, we revealed a radiating acidic layer (up to 21 nm in thickness) on the outer surface of all lysosomes, typically 0.2–0.7 pH units more acidic than the neutral cytosol. This acidic nanolayer is established and maintained primarily by TMEM175, a lysosomal H+ efflux channel associated with Parkinson’s disease. Activation of TMEM175 causes opposite pH changes on both sides of lysosomes; however, it is the juxta-lysosomal, not the luminal, acidity that determines lysosome positioning in cells with dynein adaptor RILP acting as a juxta-lysosomal pH sensor. Hence, through inside-out proton conduits, lysosomes create a steady acidic surrounding that acts as a nano-interface for cytosolic machineries to regulate organellar activities.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"62 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005981","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 : 2026-01-15DOI: 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.
{"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":"https://doi.org/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.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":""},"PeriodicalIF":21.3,"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.
{"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":"https://doi.org/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.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"244 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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