Pub Date : 2025-12-15DOI: 10.1038/s41556-025-01829-0
Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He
Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1–DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization. Zhang et al. characterize the mitochondrial inner membrane subdomain organizer (MISO) protein, which responds to inner mitochondrial membrane stress by inducing membrane subdomains promoting homeostatic fission and mtDNA degradation.
{"title":"MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains","authors":"Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He","doi":"10.1038/s41556-025-01829-0","DOIUrl":"10.1038/s41556-025-01829-0","url":null,"abstract":"Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1–DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization. Zhang et al. characterize the mitochondrial inner membrane subdomain organizer (MISO) protein, which responds to inner mitochondrial membrane stress by inducing membrane subdomains promoting homeostatic fission and mtDNA degradation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"255-267"},"PeriodicalIF":19.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759495","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}
Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress. Benito-Martínez, Salavessa and colleagues show that keratin intermediate filaments and microtubules control the three-dimensional perinuclear position of melanin-containing organelles, shielding the DNA from photodamage.
{"title":"Keratin intermediate filaments mechanically position melanin pigments for genome photoprotection","authors":"Silvia Benito-Martínez, Laura Salavessa, Anne-Sophie Macé, Myckaëla Rouabah, Nathan Lardier, Vincent Fraisier, Julia Sirés-Campos, Riddhi Atul Jani, Maryse Romao, Vanessa Roca, Charlène Gayrard, Marion Plessis, Ilse Hurbain, Cécile Nait-Meddour, Sandrine Etienne-Manneville, Etienne Morel, Michele Boniotto, Jean-Baptiste Manneville, Françoise Bernerd, Christine Duval, Graça Raposo, Cédric Delevoye","doi":"10.1038/s41556-025-01817-4","DOIUrl":"10.1038/s41556-025-01817-4","url":null,"abstract":"Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress. Benito-Martínez, Salavessa and colleagues show that keratin intermediate filaments and microtubules control the three-dimensional perinuclear position of melanin-containing organelles, shielding the DNA from photodamage.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"98-112"},"PeriodicalIF":19.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759497","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 : 2025-12-12DOI: 10.1038/s41556-025-01849-w
Cynthia A. Harris, James A. Olzmann
FSP1 is a key suppressor of lipid peroxidation and ferroptosis, yet it is largely dispensable in standard cell culture models. Two new studies now show that FSP1 becomes essential for tumour growth in vivo, establishing it as a context-specific cancer vulnerability and highlighting the therapeutic potential of FSP1 inhibition.
{"title":"In vivo models bring FSP1 inhibitors to life","authors":"Cynthia A. Harris, James A. Olzmann","doi":"10.1038/s41556-025-01849-w","DOIUrl":"10.1038/s41556-025-01849-w","url":null,"abstract":"FSP1 is a key suppressor of lipid peroxidation and ferroptosis, yet it is largely dispensable in standard cell culture models. Two new studies now show that FSP1 becomes essential for tumour growth in vivo, establishing it as a context-specific cancer vulnerability and highlighting the therapeutic potential of FSP1 inhibition.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"6-7"},"PeriodicalIF":19.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732596","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 : 2025-12-12DOI: 10.1038/s41556-025-01807-6
Caitlin E. Cornell, Aymeric Chorlay, Deepak Krishnamurthy, Nicholas R. Martin, Lucia Baldauf, Daniel A. Fletcher
Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension, they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that the target cell, rather than the macrophage, determines whether phagocytosis or trogocytosis occurs, and that macrophages do not require a distinct molecular pathway for trogocytosis. Cornell et al. show that target cells with low cortical tension induce macrophages to preferentially trogocytose, or engulf in small fragments, whereas target cells with high cortical tension tend towards phagocytosis.
{"title":"Target cell cortical tension regulates macrophage trogocytosis","authors":"Caitlin E. Cornell, Aymeric Chorlay, Deepak Krishnamurthy, Nicholas R. Martin, Lucia Baldauf, Daniel A. Fletcher","doi":"10.1038/s41556-025-01807-6","DOIUrl":"10.1038/s41556-025-01807-6","url":null,"abstract":"Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension, they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that the target cell, rather than the macrophage, determines whether phagocytosis or trogocytosis occurs, and that macrophages do not require a distinct molecular pathway for trogocytosis. Cornell et al. show that target cells with low cortical tension induce macrophages to preferentially trogocytose, or engulf in small fragments, whereas target cells with high cortical tension tend towards phagocytosis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2078-2088"},"PeriodicalIF":19.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01807-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743221","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 : 2025-12-12DOI: 10.1038/s41556-025-01818-3
Chaoyang Wu, Zheng Liu
Macrophages can either engulf targets whole (phagocytosis) or nibble them in small fragments (trogocytosis). Work now shows that this decision is controlled by cortical tension in the targets: low tension favours trogocytosis, whereas higher tension favours phagocytosis. These findings offer a new mechanical lens on immune recognition.
{"title":"Mechanical switch from nibbling to engulfment","authors":"Chaoyang Wu, Zheng Liu","doi":"10.1038/s41556-025-01818-3","DOIUrl":"10.1038/s41556-025-01818-3","url":null,"abstract":"Macrophages can either engulf targets whole (phagocytosis) or nibble them in small fragments (trogocytosis). Work now shows that this decision is controlled by cortical tension in the targets: low tension favours trogocytosis, whereas higher tension favours phagocytosis. These findings offer a new mechanical lens on immune recognition.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2043-2045"},"PeriodicalIF":19.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732595","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 : 2025-12-10DOI: 10.1038/s41556-025-01847-y
Daryl J. V. David
{"title":"Zippering against the beat","authors":"Daryl J. V. David","doi":"10.1038/s41556-025-01847-y","DOIUrl":"10.1038/s41556-025-01847-y","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2040-2040"},"PeriodicalIF":19.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723786","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 : 2025-12-10DOI: 10.1038/s41556-025-01843-2
Our study showed that lineage-determining transcription factors, such as EBF1 in B cell lymphoma and TCF1 in T cell leukaemia, shape 3D genome architecture by constraining cohesin movement. Cohesin in turn positions enhancers at the spatial centres of oncogenic loci and enables multi-enhancer regulation of key oncogenes. Together, these findings identify a unifying mechanism that links transcription factor activity, chromatin topology and oncogene control.
{"title":"Lineage-determining transcription factors EBF1 and TCF1 shape chromatin fibre folding","authors":"","doi":"10.1038/s41556-025-01843-2","DOIUrl":"10.1038/s41556-025-01843-2","url":null,"abstract":"Our study showed that lineage-determining transcription factors, such as EBF1 in B cell lymphoma and TCF1 in T cell leukaemia, shape 3D genome architecture by constraining cohesin movement. Cohesin in turn positions enhancers at the spatial centres of oncogenic loci and enables multi-enhancer regulation of key oncogenes. Together, these findings identify a unifying mechanism that links transcription factor activity, chromatin topology and oncogene control.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"11-12"},"PeriodicalIF":19.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718003","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 : 2025-12-09DOI: 10.1038/s41556-025-01820-9
Zhouyang Shen, Zaza Gelashvili, Philipp Niethammer
Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca²⁺-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN– or cPLA2–INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER–nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger. Shen, Gelashvili and Niethammer developed an inner nuclear membrane tension sensor and demonstrated that ER–nuclear membrane contiguity acts as a mechanical buffer.
{"title":"Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction","authors":"Zhouyang Shen, Zaza Gelashvili, Philipp Niethammer","doi":"10.1038/s41556-025-01820-9","DOIUrl":"10.1038/s41556-025-01820-9","url":null,"abstract":"Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca²⁺-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN– or cPLA2–INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER–nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger. Shen, Gelashvili and Niethammer developed an inner nuclear membrane tension sensor and demonstrated that ER–nuclear membrane contiguity acts as a mechanical buffer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"125-134"},"PeriodicalIF":19.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01820-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705138","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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