Molecular Biology of the Cell最新文献_第2页

Cryptosporidium aspartyl protease 2 is required for host cell egress of merozoites and male gametes. 隐孢子虫天门冬氨酸蛋白酶2是分裂子和雄性配子的寄主细胞输出所必需的。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-11-01 Epub Date: 2025-09-03 DOI: 10.1091/mbc.E25-06-0306

Bethan A Wallbank, Eleanor J Smith, Jennifer E Dumaine Carrasco, Rui Xiao, Katelyn A Walzer, Jaclyn R Riley, Boris Striepen

{"title":"Cryptosporidium aspartyl protease 2 is required for host cell egress of merozoites and male gametes.","authors":"Bethan A Wallbank, Eleanor J Smith, Jennifer E Dumaine Carrasco, Rui Xiao, Katelyn A Walzer, Jaclyn R Riley, Boris Striepen","doi":"10.1091/mbc.E25-06-0306","DOIUrl":"10.1091/mbc.E25-06-0306","url":null,"abstract":"The parasite Cryptosporidium causes severe diarrheal disease that can be life-threatening, and effective treatments are sorely lacking. Recently, aspartyl proteases (ASP) have emerged as targets with significant therapeutic potential in several related parasites, resulting in the development of multiple potent leads. ASPs are critical to the proteolytic activation and maturation of secretory proteins that parasites rely on to invade, manipulate, and upon completion of their replication cycle, exit the host cells in which they reside. The Cryptosporidium genome encodes five ASPs, which have not been previously studied. Here, we explore two of these enzymes and in genetic experiments find one, CpASP2, to be essential to parasite growth. Conditional deletion of the gene encoding this protease leads to arrest at two distinct points in the lifecycle. Cell biological studies of the mutant phenotype demonstrate that CpASP2 is required for egress of both asexual merozoites and male gametes. Mutant parasites appear to complete intracellular development yet are paralyzed and incapable of responding to stimuli that trigger motility and egress in wild-type. Ablation of CpASP2 in infected mice leads to rapid parasite clearance, highlighting the promise of CpASP2 and likely additional related enzymes as multistage targets of therapy.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar133"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Induction of postmeiotic DNA double-strand breaks by the Pnu1 endonuclease in Schizosaccharomyces pombe. 裂糖菌Pnu1内切酶诱导减数分裂后DNA双链断裂。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-11-01 Epub Date: 2025-09-03 DOI: 10.1091/mbc.E25-05-0246

Loïs Mourrain, Tiphanie Cavé, Guylain Boissonneault

{"title":"Induction of postmeiotic DNA double-strand breaks by the Pnu1 endonuclease in Schizosaccharomyces pombe.","authors":"Loïs Mourrain, Tiphanie Cavé, Guylain Boissonneault","doi":"10.1091/mbc.E25-05-0246","DOIUrl":"10.1091/mbc.E25-05-0246","url":null,"abstract":"Meiosis is a source of genetic variation in eukaryotes. Meiosis in the eukaryotic fission yeast Schizosaccharomyces pombe leads to the formation of spores that are particularly resistant to environmental stresses. In addition to external factors, internal processes may nevertheless contribute to cellular stress and impact the genome. This study investigates the role of Pnu1 as the major meiotic nuclease in S. pombe. Transcription and cellular expression of Pnu1 are regulated upon specific phases of meiosis, while its mitochondrial localization is also altered during this process. As a result, Pnu1 induces fragmentation of both genomic and mitochondrial DNA in the postmeiotic phase. This sugar-nonspecific endonuclease generates random double-strand breaks across the genome, an activity that appears to be mediated by direct interaction with chromatin. Given the high spore viability (∼95%) and the widespread occurrence of this phenomenon, this fragmentation appears to be physiological rather than apoptotic as observed in mammals. EndoG is the mammalian homologue of Pnu1 and is a caspase-independent apoptotic endonuclease that can allow cell survival. This study further describes the dynamics of Pnu1 action and supports the conclusion that Pnu1 is a major meiotic endonuclease of S. pombe responsible for a transient postmeiotic fragmentation of cellular DNA, potentially contributing to genetic variability.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar131"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PERK protein kinase facilitates keratinocyte collective cell migration by engagement with cell adhesion molecules, independent of its kinase activity. PERK蛋白激酶通过与独立于其激酶活性的细胞粘附分子结合，促进角质形成细胞的集体细胞迁移。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-11-01 Epub Date: 2025-09-24 DOI: 10.1091/mbc.E25-06-0277

Miguel Barriera Diaz, Kirk A Staschke, Anthony J Baucum, Dan F Spandau, Ronald C Wek

{"title":"PERK protein kinase facilitates keratinocyte collective cell migration by engagement with cell adhesion molecules, independent of its kinase activity.","authors":"Miguel Barriera Diaz, Kirk A Staschke, Anthony J Baucum, Dan F Spandau, Ronald C Wek","doi":"10.1091/mbc.E25-06-0277","DOIUrl":"10.1091/mbc.E25-06-0277","url":null,"abstract":"Successful cutaneous wound healing requires reepithelialization by keratinocytes using a coordinated migratory process called keratinocyte collective cell migration (KCCM). Environmental stresses such as wounding induce the integrated stress response (ISR) initiated by protein kinases that phosphorylate the α subunit of eIF2 and mitigate translational control to alleviate stress damage. We previously reported that the ISR protein kinase GCN2 (EIF2AK4) facilitates KCCM via sustained phosphorylation of eIF2α and coordinated production of reactive oxygen species and amino acid transport. In this study, we show that a second ISR protein kinase, PERK (EIF2AK3), also contributes to KCCM. PERK promotes KCCM by protein-protein interactions requiring the cytoplasmic portion of PERK but independent of its catalytic functions. To discern these PERK interactions, we used BioID proximity labeling, immunoprecipitation analyses, and immunofluorescence microscopy to show that PERK interacts with multiple cell adhesion and cytoskeletal complexes important for KCCM. PERK engages with the hemidesmosome proteins ITGA6, ITGB4, COLXVII, and the desmosome proteins JUP, DSG2, and DSG3. Loss of PERK disrupts expression and localization of these cell adhesion proteins, which alters keratinocyte morphology and increases cell-substrate and intercellular adhesions. Our results define an underappreciated scaffolding function for PERK involving cell adhesions that are critical for KCCM.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar40"},"PeriodicalIF":2.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Matrix Metalloproteinase 2 destabilizes Dally-like protein to restrict extracellular Wingless distribution. 基质金属蛋白酶2破坏dally样蛋白的稳定性，限制细胞外无翼分布。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-15 DOI: 10.1091/mbc.E22-09-0434

Indrayani Waghmare, Patrick S Page-McCaw, Andrea Page-McCaw

引用次数: 0

Localization and function of septins are susceptible to epitope tagging. septin的定位和功能容易受到表位标记的影响。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-15 DOI: 10.1091/mbc.E25-05-0217

Jack R Gregory, Ian Mikale A Llaneza, Aysha H Osmani, Haley E Gosselin, S Amirreza Sabzian, Jian-Qiu Wu

{"title":"Localization and function of septins are susceptible to epitope tagging.","authors":"Jack R Gregory, Ian Mikale A Llaneza, Aysha H Osmani, Haley E Gosselin, S Amirreza Sabzian, Jian-Qiu Wu","doi":"10.1091/mbc.E25-05-0217","DOIUrl":"https://doi.org/10.1091/mbc.E25-05-0217","url":null,"abstract":"Septins are hetero-oligomeric cytoskeletal proteins that assemble into filaments and scaffolds on the plasma membrane to aid cytokinesis, morphogenesis, and other cellular processes. Epitope tagging is widely used to study septin localization and function. However, functionality testing of tagged septins is often insufficient because of technical challenges. Fission yeast provides an ideal genetic system to test functionalities and localizations of tagged septins. mEGFP/mYFP tagged septins Spn1 and Spn4 localize exclusively to the division site as double rings during cytokinesis, but tdTomato tagged septins also localize to puncta or short linear structures across the plasma membrane. It was proposed that these additional septin structures serve as diffusion barriers and are important for the localizations and functions of several proteins, including the NDR-kinase Sid2 and active Cdc42 GTPase. By analyzing cell morphology, cytokinesis defects, and genetic interactions between tagged septins and three mutations, we find that septins are less functional with tdTomato or 3HA than other tags. Additionally, Sid2 appearance at the division site is after septins and delayed in septin deletions, contrary to previous reports. Our data re-emphasize the need for rigorous functional tests of tagged septins and for caution in interpreting function and localization data when using epitope tagged septins. [Media: see text].","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mbcE25050217"},"PeriodicalIF":2.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Vimentin Cytoskeleton Collapses in Response to the Small Molecule Inhibitor of FH2 domains (SMIFH2)-induced Electrophilic Stress. 响应FH2结构域小分子抑制剂（SMIFH2）诱导的亲电应激，Vimentin细胞骨架崩溃。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-15 DOI: 10.1091/mbc.E25-05-0228

Benjamin Capella, Katia Brock, Christopher E Turner

{"title":"Vimentin Cytoskeleton Collapses in Response to the Small Molecule Inhibitor of FH2 domains (SMIFH2)-induced Electrophilic Stress.","authors":"Benjamin Capella, Katia Brock, Christopher E Turner","doi":"10.1091/mbc.E25-05-0228","DOIUrl":"https://doi.org/10.1091/mbc.E25-05-0228","url":null,"abstract":"The type III intermediate filament protein vimentin plays an integral role in cell homeostasis and disease progression during fibrosis and cancer invasion. Previous work demonstrated that the pan-formin inhibitor SMIFH2 induced a perinuclear collapse of the vimentin network, suggesting formins may regulate vimentin cytoskeleton organization. However, despite the designed function of SMIFH2 to inhibit formin FH2 domain-actin interactions, several major off-target effects of SMIFH2 have been reported, including inhibition of myosin family ATPase activity. SMIFH2 is also highly electrophilic, potentially reacting with nucleophilic residues within proteins other than formins. Therefore, we sought to determine the mechanism by which SMIFH2 disrupts the vimentin cytoskeleton. Depletion of specific formin proteins, targeted actin cytoskeleton disruption, or myosin family ATPase inhibition failed to replicate the SMIFH2 effect on the vimentin network. However, treatment with other electrophilic reagents including prostaglandin A, reproduced the SMIFH2-mediated vimentin collapse, F-actin cytoskeletal changes, and activation of the Nrf2 stress sensory pathway. Additionally, FRAP analysis revealed that SMIFH2 inhibits vimentin filament dynamics, which was rescued by mutating the nucleophilic vimentin C328 residue. Thus, SMIFH2 disrupts the vimentin network due to its reactivity as an electrophilic species. This study reinforces the role of vimentin as a key stress sensor. [Media: see text] [Media: see text] [Media: see text] [Media: see text].","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mbcE25050228"},"PeriodicalIF":2.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transverse Cortical Microtubule Arrays Form Persistent Unipolar Domains in Hypocotyl Cells of Arabidopsis thaliana. 拟南芥下胚轴细胞的横向皮层微管阵列形成持久的单极结构域。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-15 DOI: 10.1091/mbc.E25-08-0369

Timothy Cioffi, Sidney L Shaw

{"title":"Transverse Cortical Microtubule Arrays Form Persistent Unipolar Domains in Hypocotyl Cells of Arabidopsis thaliana.","authors":"Timothy Cioffi, Sidney L Shaw","doi":"10.1091/mbc.E25-08-0369","DOIUrl":"https://doi.org/10.1091/mbc.E25-08-0369","url":null,"abstract":"Cortical microtubules influence plant cell shape by guiding cellulose deposition. Epidermal hypocotyl cells in Arabidopsis thaliana create distinct cortical array patterns to enable axial cell growth. How these array patterns are created and maintained during cell wall formation is a critical and unsolved problem in cell biology. Previous work showed that arrays aligned longitudinally with the cell's growth axis have a 'split bipolar' organization, with microtubules treadmilling toward the apical or basal ends of the cell from a region of anti-parallel overlap at the cell's midzone. The underlying order or architecture of these coaligned arrays prompted us to ask if microtubules oriented transversely to the cell's axis are organized to a similar degree. Creating new fluorescently tagged End-Binding Protein 1b (EB1b) probes to circumvent gain-of-function effects observed for GFP-EB1b, we found that transverse arrays form persistent, nearly unipolar domains of microtubules treadmilling around the short axis of the cell, independent of the EB1b probe used. Our findings reveal an organizational strategy for transverse arrays distinct from that of longitudinal arrays, with implications for the mechanisms of array pattern creation and maintenance. [Media: see text] [Media: see text] [Media: see text] [Media: see text].","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mbcE25080369"},"PeriodicalIF":2.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Conserved Disruption of Nucleocytoplasmic Compartmentalization in Meiosis is Controlled by a Kinase-Phosphatase Pair in Saccharomyces cerevisiae. 酿酒酵母菌减数分裂中核质区隔的保守破坏是由激酶-磷酸酶对控制的。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-08 DOI: 10.1091/mbc.E25-05-0229

Madison E Walsh, Keerthana Chetlapalli, Benjamin S Styler, Srigokul Upadhyayula, Grant A King, Elçin Ünal

{"title":"A Conserved Disruption of Nucleocytoplasmic Compartmentalization in Meiosis is Controlled by a Kinase-Phosphatase Pair in Saccharomyces cerevisiae.","authors":"Madison E Walsh, Keerthana Chetlapalli, Benjamin S Styler, Srigokul Upadhyayula, Grant A King, Elçin Ünal","doi":"10.1091/mbc.E25-05-0229","DOIUrl":"10.1091/mbc.E25-05-0229","url":null,"abstract":"In eukaryotic organisms, the nucleus is remodeled to accommodate the space required for chromosome segregation. Remodeling strategies range from closed division, where the nuclear envelope remains intact, to open divisions, where the nuclear envelope is temporarily disassembled. While the budding yeast Saccharomyces cerevisiae undergoes closed mitosis, its meiotic nuclear division strategy is less understood. Here we investigate nucleocytoplasmic compartmentalization during budding yeast meiosis and discover that meiosis II represents a semi-closed division marked by bidirectional mixing between the nucleus and cytoplasm. This includes nuclear entry of the Ran GTPase activating protein (RanGAP), typically cytoplasmic, although RanGAP relocalization appears to be a consequence, rather than a cause of permeability changes. This intercompartmental mixing occurs without nuclear envelope breakdown or dispersal of nucleoporins and is independent of known nuclear pore complex remodeling events. This phenomenon, termed virtual nuclear envelope breakdown (vNEBD), represents a unique mechanism distinct from other semi-closed divisions. We demonstrate that vNEBD is integrated into the meiotic program and regulated by the conserved meiotic kinase Ime2 and the meiosis-specific protein phosphatase 1 regulatory subunit, Gip1. Remarkably, the vNEBD event is conserved between S. cerevisiae and the distantly related Schizosaccharomyces pombe, indicating a fundamental role in meiosis.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mbcE25050229"},"PeriodicalIF":2.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Patient-derived Induced Pluripotent Stem Cells with a C9orf72 Expansion as a Model to Study Frontotemporal Dementia Pathologies. 患者来源的诱导多能干细胞与C9orf72扩增作为研究额颞叶痴呆病理的模型。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-08 DOI: 10.1091/mbc.E24-12-0539

Sonia Infante-Tadeo, Diane L Barber

{"title":"Patient-derived Induced Pluripotent Stem Cells with a C9orf72 Expansion as a Model to Study Frontotemporal Dementia Pathologies.","authors":"Sonia Infante-Tadeo, Diane L Barber","doi":"10.1091/mbc.E24-12-0539","DOIUrl":"10.1091/mbc.E24-12-0539","url":null,"abstract":"The neurodegenerative disorder Frontotemporal Dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 expansion causes FTD, however, remain unresolved. Diverse disease models, including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs), identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and post-mitotic. We find that patient-derived iPSCs, without being differentiated into neurons, exhibit established FTD hallmarks, including increased lysosome pH, decreased lysosomal cathepsin activity, cytosolic TDP-43 proteinopathy, and increased nuclear TFEB. Moreover, lowering lysosome pH in FTD iPSCs mitigates TDP-43 proteinopathy, suggesting a key role for lysosome dysfunction. RNA-seq reveals dysregulated transcripts in FTD iPSCs affecting calcium signaling, cell death, synaptic function, and neuronal development. We confirm differences in protein expression for some dysregulated genes not previously linked to FTD, including CNTFR (neuronal survival), Annexin A2 (anti-apoptotic), NANOG (neuronal development), and Moesin (cytoskeletal dynamics). Our findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and for drug screening to identify therapeutics.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mbcE24120539"},"PeriodicalIF":2.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The biophysical mechanism of mitochondrial pearling. 线粒体珠化的生物物理机制。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-10-08 DOI: 10.1091/mbc.E25-06-0302

Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall

{"title":"The biophysical mechanism of mitochondrial pearling.","authors":"Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall","doi":"10.1091/mbc.E25-06-0302","DOIUrl":"https://doi.org/10.1091/mbc.E25-06-0302","url":null,"abstract":"Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, \"beads-on-a-string\" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of \"pearls\" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"mbcE25060302"},"PeriodicalIF":2.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0