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| Open AccessGenetically encoded photocatalytic protein labeling enables spatially-resolved profiling of intracellular proteome
Mapping the subcellular organization of proteins is crucial for understanding their biological functions. Here, the authors develop a genetically encoded photocatalytic labeling method for profiling the subcellular proteome in multiple organelles.
- Fu Zheng
- , Chenxin Yu
- & Peng Zou
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Article
| Open AccessPeripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
Reversible mitochondrial stress leading to improved mitochondrial function (mitohormesis) has been reported as an anti-aging mechanism. Here the authors report that harmol (a beta-carboline compound) induces mitohormesis in peripheral organs, alleviates aging-related phenotypes in mice, and extends lifespan in invertebrate models.
- Luis Filipe Costa-Machado
- , Esther Garcia-Dominguez
- & Pablo J. Fernandez-Marcos
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| Open AccessViral subversion of selective autophagy is critical for biogenesis of virus replication organelles
Virus triggered lipophagy is important for flaviviral assembly and coordinated by Aup1 and the ubiquitin conjugating enzyme E2. Here, Lan et al further characterise the interplay between these proteins and how they function to modulate selective autophagy and viral replication.
- Yun Lan
- , Sophie Wilhelmina van Leur
- & Sumana Sanyal
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Article
| Open AccessZinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface
Zinc is vital to protein quality control in the early secretory pathway. Here, authors demonstrate distinct roles of the Golgi-resident zinc transporters for the maintenance of zinc homeostasis and the regulation of a zinc-dependent chaperone, ERp44.
- Yuta Amagai
- , Momo Yamada
- & Kenji Inaba
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| Open AccessOligomeric scaffolding for curvature generation by ER tubule-forming proteins
How membranes are stretched and bent around the complex structures of cellular organelles is not fully understood. Xiang and colleagues report that endoplasmic reticulum tubule-forming proteins generate membrane curvature by constructing a curved oligomeric scaffold.
- Yun Xiang
- , Rui Lyu
- & Junjie Hu
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| Open AccessTargeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct
Mutations in glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Using a fusion protein comprising GCase and a transferrin receptor antibody fragment, the authors show that the transferrin receptor pathway can be therapeutically exploited to both pass the blood-brain barrier and efficiently target lysosomal GCase deficiency.
- Alexandra Gehrlein
- , Vinod Udayar
- & Ravi Jagasia
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Article
| Open AccessStructural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria
Mitochondrial SKD3 is an essential protein disaggregase. Here, authors solve the X-ray structures of SKD3Ank domain suggesting that the disease-associated mutation Y272C leads to a disulfide bond formation that impairs SKD3 function under oxidizing conditions.
- Sukyeong Lee
- , Sang Bum Lee
- & Francis T. F. Tsai
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Article
| Open AccessConformational cycle of human polyamine transporter ATP13A2
ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson’s disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle.
- Jianqiang Mu
- , Chenyang Xue
- & Zhongmin Liu
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Article
| Open AccessMitochondrial ATP synthase as a direct molecular target of chromium(III) to ameliorate hyperglycaemia stress
Despite common use as a diabetes mellitus supplement, chromium(III)’s pharmacological effects remain unknown. We identified the Cr(III)-proteome in cells with a metalloproteomic approach and uncovered ATP synthase as a vital target to relieve hyperglycaemia stress.
- Haibo Wang
- , Ligang Hu
- & Hongzhe Sun
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Article
| Open AccessA defect in mitochondrial protein translation influences mitonuclear communication in the heart
The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.
- Feng Gao
- , Tian Liang
- & Jinghai Chen
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Article
| Open AccessTRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport
The mechanisms of microtubule-based mitochondrial transport remain poorly understood. Here, the authors show that the mitochondrial TRAK adaptors activate the dynein-dynactin complex, enhance the motility of kinesin, and can scaffold both motors to control bidirectional transport.
- John T. Canty
- , Andrew Hensley
- & Ahmet Yildiz
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Article
| Open AccessSugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.
- Pei Ying Ng
- , Amy B. P. Ribet
- & Nathan J. Pavlos
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Article
| Open AccessCholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols
Dumesnil et al. report that cholesterol esters (CE), which only melt above body temperature, form supercooled liquid crystalline lipid droplets (LD). Triacylglycerols (TG) solubilize CE to help CE LD nucleation. Through clustering TGs in the ER membrane, seipin controls CE LD nucleation sites.
- Calvin Dumesnil
- , Lauri Vanharanta
- & Abdou Rachid Thiam
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Article
| Open AccessSingle-cell atavism reveals an ancient mechanism of cell type diversification in a sea anemone
Understanding how new cell types arise is essential for understanding the evolution of animal diversity. This study shows that a single gene, NvSox2, acts as a simple switch controlling the development of two alternative types of stinging cells in the sea anemone Nematostella vectensis.
- Leslie S. Babonis
- , Camille Enjolras
- & Mark Q. Martindale
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Article
| Open AccessThe p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition
Inter-organellar contacts are hubs for several critical cellular processes, such as lipid synthesis. Here Ganji et al. show that the p97-UBXD8 complex modulates contacts by regulating membrane lipid composition and saturation.
- Rakesh Ganji
- , Joao A. Paulo
- & Malavika Raman
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Article
| Open AccessMicrotubule nucleation and γTuRC centrosome localization in interphase cells require ch-TOG
The molecular mechanisms underpinning the organization of microtubule arrays remain unclear. Here the authors show that in human cells, the microtubule polymerase ch-TOG promotes nucleation of microtubules at the interphase centrosome and the Golgi through a mechanism that involves transient interaction with the microtubule nucleator γTuRC.
- Aamir Ali
- , Chithran Vineethakumari
- & Jens Lüders
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Article
| Open AccessDynamics of CLIMP-63 S-acylation control ER morphology
A key player in the formation of endoplasmic reticulum sheets is CLIMP-63, but mechanistic details remained elusive. Here authors combined cellular experiments and mathematical modelling to show that S-acylation of CLIMP-63 regulates its function by mediating its oligomerisation, turnover, and localisation.
- Patrick A. Sandoz
- , Robin A. Denhardt-Eriksson
- & F. Gisou van der Goot
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Article
| Open AccessThe metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans
Understanding how metabolites modulate longevity is crucial for reducing aging-related disease. Here, the authors demonstrate that α-ketobutyrate exhibits an anti-aging effect by coordinating NAD + -SIRT1 signaling and peroxisome function.
- Nan Wu
- , Yi-Cheng Ma
- & Cheng-Gang Zou
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| Open AccessDisruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
Some forms of mitochondrial dysfunction can cause sterile inflammation, but the way in which it might affect muscle fitness is not well understood. Here, the authors show that altered mitochondrial dynamics can cause the production of mitochondrial DNA-driven inflammatory signals mediated by endosome-mitochondria contacts, leading to muscle inflammation, atrophy, reduced physical performance and enhanced exercise-induced inflammatory responses.
- Andrea Irazoki
- , Isabel Gordaliza-Alaguero
- & Antonio Zorzano
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| Open AccessDynamic assembly of DNA-ceria nanocomplex in living cells generates artificial peroxisome
Artificial organelles can potentially be used support cellular functions, but there is a trade-off between cellular uptake and cellular retention. Here, the authors report the dynamic assembly of DNA-ceria-based artificial peroxisomes in cells, and show they can be used to reduce intracellular ROS.
- Chi Yao
- , Yuwei Xu
- & Dayong Yang
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Article
| Open AccessCryo-electron tomography reveals structural insights into the membrane remodeling mode of dynamin-like EHD filaments
Eps15-homology domain containing proteins comprise a family of dynamin-related ATPases. Here, Melo et al. use cryo-electron tomography to determine the membrane-bound EHD4 structure, therefore clarifying the membrane binding and oligomerization mode.
- Arthur A. Melo
- , Thiemo Sprink
- & Oliver Daumke
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| Open AccessThe role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction
Impaired liver metabolic function is related to mortality in severely malnourished children. Here the authors report a role for the tryptophan-NAD + pathway in reduced hepatic mitochondrial function and liver steatosis in a mouse model of severe malnutrition.
- Guanlan Hu
- , Catriona Ling
- & Robert H. J. Bandsma
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Article
| Open AccessNuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation
Cellular metabolism is important in pluripotency and cell fate regulation. Here, authors observe chromatin remodeling followed by TCA enzyme translocation from the mitochondria to the nucleus, demonstrating pluripotency regulation by mitochondria to nucleus retrograde signaling.
- Wei Li
- , Qi Long
- & Xingguo Liu
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| Open AccessAnterograde signaling controls plastid transcription via sigma factors separately from nuclear photosynthesis genes
Photoreceptors in the nucleus control plastid transcription by utilizing sigma factors as nucleus-to-plastid signals in parallel with the light regulation of nuclear photosynthesis genes.
- Youra Hwang
- , Soeun Han
- & Meng Chen
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Article
| Open AccessLysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism
Extensive lysosomal damage can result in cell death but how limited protease leakage affects cytoplasmic organelles in viable cells is not well understood. Here the authors show that limited lysosomal damage leads to changes in the mitochondrial proteome and the modulation of macrophage immunometabolism.
- Claudio Bussi
- , Tiaan Heunis
- & Maximiliano G. Gutierrez
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Article
| Open AccessmTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity
Lung branching requires differentiation of progenitor cells to be coordinated with morphogenetic events. Zhang et al. find that loss of mTORC1 signaling in the distal SOX9+ lung progenitors reduces mitochondrial capacity and ATP production, thus disrupting the formation of the conducting airways without affecting the development of the gas exchange unit.
- Kuan Zhang
- , Erica Yao
- & Pao-Tien Chuang
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Article
| Open AccessInterruption of post-Golgi STING trafficking activates tonic interferon signaling
Microbial DNA is recognized by the cGAS-STING pathway, which leads to a type I interferon response. Here authors show that a basal flux of interferon activation could also be triggered by interference with STING trafficking from the Golgi apparatus to the lysosomes.
- Xintao Tu
- , Ting-Ting Chu
- & Nan Yan
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| Open AccessA multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins
Odor stimuli are transduced in cilia of olfactory sensory neurons. Here the authors identify an odor stimulus-regulated organelle that specifically stores and releases transduction proteins in the dendrite.
- Devendra Kumar Maurya
- , Anna Berghard
- & Staffan Bohm
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| Open AccessDominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish
Disruptions to the ER-Golgi network can lead to neurodevelopmental disorders, though our understanding of these Golgipathies remains incomplete. Here Lauri, Tartaglia and colleagues show that ARF3 mutations cause a rare pediatric neurological disorder and perform detailed molecular characterization in fish.
- Giulia Fasano
- , Valentina Muto
- & Marco Tartaglia
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Article
| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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| Open AccessCapture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism
The formation and dissolution of ER-Mitochondria contacts is unclear. Here, authors show that the IP3 receptor traffics in and out of the contacts and, when trapped, improves calcium signaling to stimulate energy metabolism.
- Máté Katona
- , Ádám Bartók
- & György Hajnóczky
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Article
| Open AccessMitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA
Mitochondrial quality control mechanisms prevent damage accumulation, including in mitochondrial DNA (mtDNA). Here, Sen et al. show that altered mtDNA elicits local rearrangements in mitochondrial membrane potential and cristae structure, with mtDNA eliminated through VPS35 endosomes.
- Ayesha Sen
- , Sebastian Kallabis
- & David Pla-Martín
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Article
| Open AccessIdentification of evolutionarily conserved regulators of muscle mitochondrial network organization
Mitochondrial networks are carefully positioned to facilitate energy distribution within muscle cells. Here they show that energetic demands and conserved transcription factors regulate mitochondrial network organization and contractile phenotypes independently in Drosophila.
- Prasanna Katti
- , Peter T. Ajayi
- & Brian Glancy
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| Open AccessMitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure
Mitochondria power the beating heart. Here, Donnarumma et al. show that loss of the inner mitochondrial membrane protein MTFP1 in cardiomyocytes reduces bioenergetic efficiency and cell death resistance leading to heart failure in mice.
- Erminia Donnarumma
- , Michael Kohlhaas
- & Timothy Wai
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Article
| Open AccessHuman mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control
How translation termination is achieved for the non-conventional mtDNA-encoded COX1 and ND6 was so far unknown. Here, Nadler et al. address this question by assessing the functions and specificity of the mitochondrial release factors mtRF1 and mtRF1a.
- Franziska Nadler
- , Elena Lavdovskaia
- & Ricarda Richter-Dennerlein
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| Open AccessCross-linking of the endolysosomal system reveals potential flotillin structures and cargo
Protein complexes play a decisive role for lysosomal function. Here, the authors use cross-linking mass spectrometry and integrative modeling to investigate lysosomes and early endosomes; characterizing protein interactions, structures, and the cargo of flotillin-mediated endocytosis.
- Jasjot Singh
- , Hadeer Elhabashy
- & Dominic Winter
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| Open AccessSpatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
Methods to assess organellar content are important. Here, Park et al develop a method for rapid isolation of early/sorting endosomes and demonstrate the application of the approach for analysis of endosomal proteomes and lipidomes, and for analysis of APP processing to Aβ via β and γ-Secretases.
- Hankum Park
- , Frances V. Hundley
- & J. Wade Harper
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| Open AccessMitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles
How different physical configurations between sarcomeres and mitochondria alter energetic support for contractile function of skeletal muscle is not clear. Here the authors use advanced 3D imaging and analysis techniques to show how space is made for mitochondria within the tightly packed sarcomere networks of striated muscle cells.
- Prasanna Katti
- , Alexander S. Hall
- & Brian Glancy
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Article
| Open AccessResolving subcellular pH with a quantitative fluorescent lifetime biosensor
Measuring sub-cellular pH with high accuracy and spatiotemporal resolution remains challenging. Here, Johnston and co-workers develop a pH biosensor that combines the pH dependant fluorescent lifetime of mApple with deep learning to accurately determine sub-cellular pH in individual vesicles.
- Joshua J. Rennick
- , Cameron J. Nowell
- & Angus P. R. Johnston
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Article
| Open AccessThe coilin N-terminus mediates multivalent interactions between coilin and Nopp140 to form and maintain Cajal bodies
Cajal bodies are membraneless organelles scaffolded by coilin protein. Here, coilin–coilin and coilin–Nopp140 interaction sites are identified and perturbed, revealing coilin’s capacity to form long fibrils and be remodeled into spherical structures.
- Edward Courchaine
- , Sara Gelles-Watnick
- & Karla M. Neugebauer
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Article
| Open AccessANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing
A subset of mitochondrial transcripts is not flanked by tRNAs and thus does not conform to the canonical mode of processing. Here, Clemente et al. demonstrate that phosphatase activity of ANGEL2 is required for correct processing of these transcripts.
- Paula Clemente
- , Javier Calvo-Garrido
- & Anna Wredenberg
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Article
| Open AccessMcaA and McaB control the dynamic positioning of a bacterial magnetic organelle
Magnetotactic bacteria use intracellular chains of ferrimagnetic nanocrystals, produced within magnetosome organelles, to align and navigate along the geomagnetic field. Here, Wan et al. identify two proteins involved in magnetosome positioning in Magnetospirillum magneticum, homologs of which are widespread among magnetotactic bacteria.
- Juan Wan
- , Caroline L. Monteil
- & Arash Komeili
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Article
| Open AccessStructure and activity of particulate methane monooxygenase arrays in methanotrophs
Particulate methane monooxygenase (pMMO) is the main enzyme used by methanotrophs. Here, the authors determined the native structure of pMMO by cryo-electron tomography, revealing lipid-stabilized features and a higher-order hexagonal array arrangement in intact cells.
- Yanan Zhu
- , Christopher W. Koo
- & Peijun Zhang
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Article
| Open AccessThe nucleolus is the site for inflammatory RNA decay during infection
The nucleolus is the traditional site for ribosomal RNA biogenesis. Here, the authors find that the nucleolus is a site of inflammatory pre-mRNA turnover and elucidated how immune homeostasis can be maintained by controlling inflammatory gene expression.
- Taeyun A. Lee
- , Heonjong Han
- & Boyoun Park
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Article
| Open AccessMapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation
Autophagy is known to impact CD4+ T cell proliferation but the identity of autophagosomal components remain unclear. Here the authors leverage a transgenic mouse model to assess the autophagosomal compartment and identify interleukin-7 receptor-α as a key cargo in proliferating CD4+ T cells.
- Dingxi Zhou
- , Mariana Borsa
- & Anna Katharina Simon
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Article
| Open AccessProtein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy
Mitophagy activation is mediated by mitochondrial depolarization. Here, the authors show that mitochondrial protein misfolding can activate mitophagy in a depolarization-independent manner mediated by a protein import reduction.
- Jonas Benjamin Michaelis
- , Melinda Elaine Brunstein
- & Christian Münch
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Article
| Open AccessStructural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA
Mitochondrial tRNAs are indispensable and yet underwent an extreme mutational erosion. The authors report the structures of a mitochondrial aaRS-tRNA complex and show how the most degenerated of all human mtRNAs is recognized by its cognate synthetase to maintain mitochondrial gene expression.
- Bernhard Kuhle
- , Marscha Hirschi
- & Paul Schimmel
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| Open AccessCytoplasmic forces functionally reorganize nuclear condensates in oocytes
Cytoskeletal activity generates mechanical forces known to agitate and displace membrane-bound organelles in the cytoplasm. In oocytes, Al Jord et al. discover that these cytoplasmic forces functionally remodel nuclear RNA-processing condensates across scales for developmental success.
- Adel Al Jord
- , Gaëlle Letort
- & Marie-Hélène Verlhac
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Article
| Open AccessLysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
Release of α-synuclein aggregates by neurons instigates spread of pathology in synucleinopathies, but the mechanism remains unclear. Here the authors show that neuronally generated α-synuclein aggregates accumulate within neuronal lysosomes and are released via SNARE-dependent lysosomal exocytosis.
- Ying Xue Xie
- , Nima N. Naseri
- & Manu Sharma