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| Open AccessMitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis
Mitochondrial function is linked to lifespan. Here the authors show that inhibition of mitochondrial protein import leads to a reduction in mitochondrial abundance and extends lifespan in Caenorhabditis elegans via activation of glycolysis and de novo serine biosynthesis.
- Eirini Lionaki
- , Ilias Gkikas
- & Nektarios Tavernarakis
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Article
| Open AccessTAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A
Mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular signals including exercise. TAZ is revealed as a novel stimulator for mitochondrial biogenesis and facilitates exercise-induced muscle adaptation.
- Jun-Ha Hwang
- , Kyung Min Kim
- & Jeong-Ho Hong
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Article
| Open AccessLima1 mediates the pluripotency control of membrane dynamics and cellular metabolism
How pluripotency transcription factors regulate the cellular architecture and energetics has remained largely unknown. Here the authors identify Lima1 as a key effector that mediates the pluripotency control of membrane dynamics and cellular metabolism.
- Binyamin Duethorn
- , Fabian Groll
- & Ivan Bedzhov
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Article
| Open AccessAberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis
CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.
- Irene Lopez-Fabuel
- , Marina Garcia-Macia
- & Juan P. Bolaños
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Article
| Open AccessNuclear and mitochondrial DNA editing in human cells with zinc finger deaminases
Base editing in nuclear DNA and mitochondrial DNA (mtDNA) is broadly useful for biomedical research, medicine, and biotechnology. Here the authors present zinc finger deaminases which catalyze targeted C-to-T base conversions without inducing unwanted indels in human cells.
- Kayeong Lim
- , Sung-Ik Cho
- & Jin-Soo Kim
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Article
| Open AccessThe RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation
RNA modifications are key regulators of RNA functions. Here, the authors identify METTL8 as the enzyme installing m3C32 in mitochondrial tRNAThr/Ser(UCN). Lack of these modifications affects tRNA structure and impairs mitochondrial translation.
- Nicole Kleiber
- , Nicolas Lemus-Diaz
- & Markus T. Bohnsack
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Article
| Open AccessLipid droplet availability affects neural stem/progenitor cell metabolism and proliferation
Lipid droplets (LDs) are central to lipid metabolism, which is known to regulate neural stem cell behavior. Here, the authors show that LDs influence neural stem cell proliferation and metabolic activity and change upon differentiation or quiescence.
- Mergim Ramosaj
- , Sofia Madsen
- & Marlen Knobloch
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Article
| Open AccessAcute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity
Ryanodine receptor type 1 (RyR1) are involved in skeletal muscle contraction. Here, the authors show that a transient calcium leak in response to exercise-induced post translational modifications of RyR1 causes mitochondrial remodeling to improve respiration.
- Nadège Zanou
- , Haikel Dridi
- & Nicolas Place
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Article
| Open AccessSpatial control of avidity regulates initiation and progression of selective autophagy
The molecular principles governing the initiation of autophagosome formation are not clearly understood. Here we show that the vacuolar protein Vac8 coordinates this process by promoting an avidity-driven assembly of several autophagy factors.
- David M. Hollenstein
- , Mariya Licheva
- & Claudine Kraft
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Article
| Open AccessHow to build a ribosome from RNA fragments in Chlamydomonas mitochondria
Mitoribosomes are remarkably diverse in their structures and compositions. Here the authors combine biochemistry, genetics, single particle cryo-electron microscopy and in situ cryo-electron tomography to reveal the mitochondrial ribosome of Chlamydomonas reinhardtii as an extreme example of evolution and species-specific adaptation.
- Florent Waltz
- , Thalia Salinas-Giegé
- & Yaser Hashem
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Article
| Open AccessAcetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming
Lactic acidosis is a metabolic state that occurs in injured tissues. Here the authors show that macrophages, in order to remain functional in acidosis, reduce their mitochondrial mass by mitophagy and rely on autophagy for survival, with mitochondrial integrity retained using acetoacetate as alternative fuel.
- Clément Adam
- , Léa Paolini
- & Pascale Jeannin
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Article
| Open Access2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA
It has been a longstanding goal to promote the propagation of functional mitochondrial DNAs at the expense of pathological molecules in cells where the two species coexist. Here, the authors show that restricting the availability of glucose and glutamine can achieve this outcome.
- Boris Pantic
- , Daniel Ives
- & Antonella Spinazzola
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Article
| Open AccessCoalescence and directed anisotropic growth of starch granule initials in subdomains of Arabidopsis thaliana chloroplasts
Starch is the major form of energy storage in plant cells and forms discrete, semi-crystalline granules within plastids. Here the authors use electron tomography and nanoSIMS to show that Arabidopsis starch granules initiate in stromal pockets between thylakoid membranes that coalesce before growing anisotropically.
- Léo Bürgy
- , Simona Eicke
- & Samuel C. Zeeman
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Article
| Open AccessN-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization
[2Fe-2S] protein cofactors are essential for life and are synthesized on ISCU2 scaffolds. Here, the authors show that hydrophobic interaction of two conserved N-terminal tyrosines induces ISCU2 dimerization and concomitant [2Fe-2S] cluster synthesis.
- Sven-A. Freibert
- , Michal T. Boniecki
- & Roland Lill
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Article
| Open AccessFunctionally distinct roles for eEF2K in the control of ribosome availability and p-body abundance
Processing bodies are phase separated compartments enriched in translationally repressed mRNAs. Here, Smith et al. show that, in sensory neurons, eukaryotic elongation factor 2 kinase (eEF2K) plays key roles in the regulation of processing body abundance and the formation of translationally inactive ribosomes.
- Patrick R. Smith
- , Sarah Loerch
- & Zachary T. Campbell
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Article
| Open AccessThe autophagy protein ATG9A enables lipid mobilization from lipid droplets
ATG9A is transmembrane autophagic machinery protein that delivers phospholipids to expanding autophagosomes. Mailler et al. show that ATG9A is required to mobilize lipids from lipid droplets for autophagosome expansion as well as mitochondrial fatty acid import and β-oxidation.
- Elodie Mailler
- , Carlos M. Guardia
- & Juan S. Bonifacino
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Article
| Open AccessSingle cell genomics reveals plastid-lacking Picozoa are close relatives of red algae
The origin of primary plastids in an ancestor of Archaeplastida gave eukaryotes photosynthetic capabilities. This study used single-cell genomics and phylogenomics to infer the evolutionary origin of the plastid-lacking phylum Picozoa, a group of marine microbial heterotrophic eukaryotes, showing that they belong to the Archaeplastida and changing our understanding of plastid evolution.
- Max E. Schön
- , Vasily V. Zlatogursky
- & Fabien Burki
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Article
| Open AccessmTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation
Autophagy relies on coordinated fusion of organelle membranes, although the interplay between the regulatory machinery is not well studied. Here, the authors show that SNARE complex formation is inhibited by mTORC1 phosphorylation of VAMP8, which prevents autophagosome-lysosome fusion.
- Hong Huang
- , Qinqin Ouyang
- & Rong Liu
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Article
| Open AccessThe phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes
Macropinocytosis permits the cellular uptake of fluids and nutrients via macropinosomes. Here, the authors show that Phafin2 is required for the formation of macropinosomes and permits their transit through dense actin networks.
- Kay Oliver Schink
- , Kia Wee Tan
- & Harald Stenmark
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Article
| Open AccessConstitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation
Heteroplasmic mtDNA mutations cause disease in humans. Here, Chung et al find the PI3K-Akt-mTORC1 pathway constitutively activated in cells with the heteroplasmic m.3243 A > G mutation, and inhibition of the pathway cell autonomously reduces mutant mtDNA load and rescues mitochondrial bioenergetics.
- Chih-Yao Chung
- , Kritarth Singh
- & Michael R. Duchen
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Article
| Open AccessKinetic and structural roles for the surface in guiding SAS-6 self-assembly to direct centriole architecture
The centriole exhibits an evolutionarily conserved 9-fold radial symmetry that stems from a cartwheel containing vertically stacked ring polymers that harbor 9 homodimers of the protein SAS-6. Here the authors show how dual properties inherent to surface-guided SAS-6 self-assembly possess spatial information that dictates correct scaffolding of centriole architecture.
- Niccolò Banterle
- , Adrian P. Nievergelt
- & Pierre Gönczy
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Article
| Open AccessRIPK1 regulates starvation resistance by modulating aspartate catabolism
RIPK1 is critical for normal development and cell death. Here, the authors identify a metabolic role for RIPK1 in aspartate homeostasis, as increased aspartate levels in RIPK1-deficient cells inhibits starvation-induced autophagy by ULK1.
- Xinyu Mei
- , Yuan Guo
- & Zheng-Jiang Zhu
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Article
| Open AccessPDZD-8 and TEX-2 regulate endosomal PI(4,5)P2 homeostasis via lipid transport to promote embryogenesis in C. elegans
Cellular membranes have distinct lipid compositions despite intermixing, and it is unclear why plasma membrane lipids do not accumulate on endosomes. Here, the authors use the C. elegans embryo to identify lipid transfer proteins and phosphatases that are critical for endosomal lipid homeostasis.
- Darshini Jeyasimman
- , Bilge Ercan
- & Yasunori Saheki
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Article
| Open Accessp107 mediated mitochondrial function controls muscle stem cell proliferative fates
The connection between cell cycle, metabolic state and mitochondrial activity is unclear. Here, the authors show that p107 represses mitochondrial transcription and ATP output in response to glycolytic byproducts, causing metabolic control of the cell cycle rate in myogenic progenitors.
- Debasmita Bhattacharya
- , Vicky Shah
- & Anthony Scimè
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Article
| Open AccessMechanism of lipid droplet formation by the yeast Sei1/Ldb16 Seipin complex
Lipid droplet biogenesis is orchestrated by the conserved membrane protein Seipin via an unknown mechanism. Here, the authors use structural, biochemical and molecular dynamics simulation approaches to reveal the mechanism of lipid droplet formation by the yeast Seipin Sei1 and its partner Ldb16.
- Yoel A. Klug
- , Justin C. Deme
- & Pedro Carvalho
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Article
| Open AccessA plastid two-pore channel essential for inter-organelle communication and growth of Toxoplasma gondii
Two-pore channels (TPCs) are cation channels that localize to acidic organelles to regulate Ca2+ dependent events. Here, Li et al. characterize a TPC from Toxoplasma gondii(TgTPC) that localizes to the apicoplast, is critical for maintaining its integrity and relevant for Ca2+ uptake from the ER through stabilizing inter-organelle contact.
- Zhu-Hong Li
- , Thayer P. King
- & Silvia N. J. Moreno
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Article
| Open AccessMapping protein interactions in the active TOM-TIM23 supercomplex
The TOM and TIM23 complexes facilitate the transport of nuclear-encoded proteins into the mitochondrial matrix. Here, the authors use a stalled client protein to purify the translocation supercomplex and gain insight into the TOM-TIM23 interface and the mechanism of protein handover from the TOM to the TIM23 complex.
- Ridhima Gomkale
- , Andreas Linden
- & Peter Rehling
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Article
| Open AccessIn situ cryo-electron tomography reveals gradient organization of ribosome biogenesis in intact nucleoli
The large and small subunits of the ribosome are synthesized independently within the nucleolus — a membrane-less compartment within the nucleus — before being exported into the cytoplasm. Here, the authors use in situ cryo-ET to observe ribosome maturation and reveal the native organization of the nucleolus.
- Philipp S. Erdmann
- , Zhen Hou
- & Wolfgang Baumeister
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Article
| Open AccessORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division
Membrane contact sites between organelles have specialized functions that are only beginning to be understood. Here, the authors show that ORP1L mediates lysosome recruitment and PI(4)P signaling at endoplasmic reticulum-lysosome-mitochondria three-way contact sites involved in mitochondrial division.
- Maxime Boutry
- & Peter K. Kim
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Article
| Open AccessSpatiotemporally-resolved mapping of RNA binding proteins via functional proximity labeling reveals a mitochondrial mRNA anchor promoting stress recovery
Proximity labeling is used to map and discover proteins in specific subcellular compartments. Here the authors combine APEX-mediated proximity labeling with organic-aqueous phase separation to identify nuclear, nucleolar, and outer mitochondrial membrane RNA binding proteins.
- Wei Qin
- , Samuel A. Myers
- & Alice Y. Ting
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Article
| Open AccessPERM1 interacts with the MICOS-MIB complex to connect the mitochondria and sarcolemma via ankyrin B
Mitochondria in skeletal muscle have distinct localization and properties through unclear mechanisms. Here, the authors use complexome profiling and immunoprecipitations to identify PERM1 as a MICOS-MIB complex interactor that also binds ankyrin B, suggesting PERM1 directs the mitochondria to the membrane.
- Theresa Bock
- , Clara Türk
- & Marcus Krüger
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Article
| Open AccessDefining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase
The nature of the mitochondrial permeability transition pore (PTP) is still under debate. Here, through genetically modified F-ATP synthase, the authors show that PTP formation can be mediated by F-ATP synthase or by adenine nucleotide translocator, suggesting the existence of distinct but related permeability pathways.
- Andrea Carrer
- , Ludovica Tommasin
- & Paolo Bernardi
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Article
| Open AccessUbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae
Coenzyme Q (CoQ) is a lipid made in the inner mitochondrial membrane with antioxidant roles throughout the cell, but regulation of its cellular distribution is unclear. Here the authors identify two proteins that have reciprocal CoQ trafficking functions to help coordinate CoQ localization in yeast.
- Zachary A. Kemmerer
- , Kyle P. Robinson
- & David J. Pagliarini
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Article
| Open AccessSNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum
Endoplasmic reticulum (ER)-interorganelle membrane contact sites have emerged as key regulators of organelle dynamics. Here, the authors report that the ER-resident protein SNX19 mediates ER-endolysosome membrane contacts to maintain the perinuclear distribution of endolysosomes and restrict their motility.
- Amra Saric
- , Spencer A. Freeman
- & Juan S. Bonifacino
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Article
| Open AccessA distinct assembly pathway of the human 39S late pre-mitoribosome
Assembly of the mitoribosome requires assistance from numerous specialized factors. Here, structures of the human 39S late assembly intermediates identify several assembly factors which keep the 16S rRNA in immature conformations, and reveal deacylated tRNA in the ribosomal E-site, suggesting a role in 39S assembly.
- Jingdong Cheng
- , Otto Berninghausen
- & Roland Beckmann
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Article
| Open AccessKRAP tethers IP3 receptors to actin and licenses them to evoke cytosolic Ca2+ signals
Calcium signals initiated by IP3 receptors in ER membranes regulate most cellular activities. Here, the authors show that KRas-induced actininteracting protein (KRAP) tethers a small subset of IP3 receptors to actin and licenses them to evoke cytosolic calcium signals.
- Nagendra Babu Thillaiappan
- , Holly A. Smith
- & Colin W. Taylor
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Article
| Open AccessER – lysosome contacts at a pre-axonal region regulate axonal lysosome availability
In neurons and other cells, contacts between organelles regulates function and subcellular organization, but the precise mechanisms and effects are unclear. Here the authors show that endoplasmic reticulum (ER) tubules in the soma of neurons regulate lysosome localization and function by regulating lysosomal fission, suggesting a role for ER – lysosome inter-organelle membrane contact sites in lysosomal axonal availability.
- Nazmiye Özkan
- , Max Koppers
- & Ginny G. Farías
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Article
| Open AccessSpecificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9
Extracellular vesicles (EVs) play a role in intercellular communication, however the precise biogenesis of different populations of EVs are not clear. Here, the authors follow the intracellular trafficking of two proteins before their secretion in EVs and report the biogenesis and protein markers of EV subtypes: ectosomes budding from the plasma membrane as well as exosomes from late endosomes.
- Mathilde Mathieu
- , Nathalie Névo
- & Clotilde Théry
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Article
| Open AccessGlobal kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery
Mitochondrial protein import is mediated by the translocase of the outer membrane (TOM), through which nearly all precursors traverse. Here, the authors perform global in vitro kinome profiling and by this identify that DYRK1A phosphorylates TOM70 and promotes import.
- Corvin Walter
- , Adinarayana Marada
- & Chris Meisinger
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Article
| Open AccessTSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Tuberous sclerosis complex (TSC) is a multiorgan disease that can lead to hyperactive mTORC1 due to deficient TSC1 or TSC2 protein function. Here, the authors find that despite high mTORC1 activity, TFEB localizes to the nucleus and drives lysosomal gene expression via a non-canonical Rag-dependent mechanism.
- Nicola Alesi
- , Elie W. Akl
- & Elizabeth P. Henske
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Article
| Open AccessPGRL2 triggers degradation of PGR5 in the absence of PGRL1
It is currently thought that the thylakoid proteins PGRL1 and PGR5 form a complex to mediate cyclic electron flow (CEF) around photosystem I. Here the authors show that CEF can in fact be mediated by PGR5 alone and that PGRL1 and the homologous PGRL2 modify the process by modulating PGR5 activity and stability.
- Thilo Rühle
- , Marcel Dann
- & Dario Leister
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Article
| Open AccessStructural basis for the ARF GAP activity and specificity of the C9orf72 complex
C9orf72:SMCR8:WDR41 complex has been reported to have GAP activity for both ARF family proteins and the RAB proteins RAB8A and RAB11A. Here the authors provide structural and biochemical evidence for a specific function of the C9orf72 complex as an ARF GAP, and a structural framework for the GAP activity of the longin-containing GAP family.
- Ming-Yuan Su
- , Simon A. Fromm
- & James H. Hurley
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Article
| Open AccessDistinct mechanisms of the human mitoribosome recycling and antibiotic resistance
High-resolution cryo-EM structures and biochemical analyses of the human mitoribosome, in complex with mitochondria-specific factors mediating mitoribosome recycling, RRFmt and EF-G2mt, offer insight into mechanisms of mitoribosome recycling and resistance to antibiotic fusidic acid.
- Ravi Kiran Koripella
- , Ayush Deep
- & Rajendra K. Agrawal
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Article
| Open AccessPerilipin 5 links mitochondrial uncoupled respiration in brown fat to healthy white fat remodeling and systemic glucose tolerance
Perilipin 5 is a lipid droplet protein that interacts with PGC1α in the nucleus to regulate mitochondrial metabolism. Here the authors use genetically engineered mouse models to determine the physiologic role of Perilipin 5, and show that it regulates mitochondrial adaptations to cold, as well as systemic energy metabolism.
- Violeta I. Gallardo-Montejano
- , Chaofeng Yang
- & Perry E. Bickel
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Article
| Open AccessCytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease
Mitochondrial and lysosomal dysfunction are central to Parkinson’s disease (PD) pathogenesis. Here, the authors show mitochondrial dsDNA in the cytosol in cellular and Zebrafish models of PD induces cytotoxicity and neurodegeneration; knock-down of IFI16, a cytosolic dsDNA sensor, rescues cytotoxicity, as does overexpression of lysosomal DNAse II.
- Hideaki Matsui
- , Junko Ito
- & Akiyoshi Kakita
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Article
| Open AccessINPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
The PI(3,4)P2 4-phosphatase, INPP4B, functions as a tumour suppressor in triple negative breast cancer. Here, the authors show that INPP4B enhances proliferation and growth of PIK3CA-mutant ER+ breast cancers by promoting PI3Kα-dependent late endosome formation and trafficking that leads to the activation of Wnt/β-catenin signalling.
- Samuel J. Rodgers
- , Lisa M. Ooms
- & Christina A. Mitchell
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Article
| Open AccessAnalysis of diverse eukaryotes suggests the existence of an ancestral mitochondrial apparatus derived from the bacterial type II secretion system
Bacteria use the type 2 secretion system to secrete enzymes and toxins across the outer membrane to the environment. Here the authors analyse the T2SS pathway in three protist lineages and suggest that the early mitochondrion may have been capable of secreting proteins into the cytosol.
- Lenka Horváthová
- , Vojtěch Žárský
- & Pavel Doležal
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Article
| Open AccessMitofusin-2 stabilizes adherens junctions and suppresses endothelial inflammation via modulation of β-catenin signaling
Endothelial tissues must have intact barrier function, but this may be disrupted during inflammation. Here, the authors show that the mitochondrial protein Mitofusin-2 stabilizes cell–cell adherens junctions in endothelial cells during homeostasis and binds the transcriptional activator β-catenin upon inflammatory stimulation.
- Young-Mee Kim
- , Sarah Krantz
- & Jalees Rehman
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Article
| Open AccessN-aryl pyrido cyanine derivatives are nuclear and organelle DNA markers for two-photon and super-resolution imaging
It is challenging to develop DNA probes that allow staining of both organelle and nuclear DNA, are compatible with super resolution imaging and avoid UV-light photo-excitation. The authors overcome these issues with N-aryl pyrido cyanine derivatives showing high DNA specificity and membrane permeability.
- Kakishi Uno
- , Nagisa Sugimoto
- & Yoshikatsu Sato