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1
المؤلفون: Aleksandra Filipovska, Rui Ruan, Hiroshi Takayanagi, Qing Jiang, Junjie Gao, An Qin, Tak Sum Cheng, Ming H. Zheng, Changqing Zhang, John M. Papadimitriou, Xiang Gao, Jian Q. Feng, Qiyang Wang, Kerong Dai, Delin Liu, Jun Yuan
المصدر: Science Advances
مصطلحات موضوعية: MFN2, GTPase, Mitochondrion, Endoplasmic Reticulum, Osteocytes, Cell Line, GTP Phosphohydrolases, Mice, 03 medical and health sciences, Mitofusin-2, 0302 clinical medicine, medicine, Animals, Homeostasis, Research Articles, Tissue homeostasis, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Microscopy, Confocal, Multidisciplinary, Chemistry, Endoplasmic reticulum, SciAdv r-articles, Cell Biology, Mitochondria, Cell biology, medicine.anatomical_structure, Osteocyte, 030217 neurology & neurosurgery, Research Article
الوصف: Intercellular mitochondrial transfer mediated by the endoplasmic reticulum is essential for tissue homeostasis.
Mitochondrial transfer plays a crucial role in the regulation of tissue homeostasis and resistance to cancer chemotherapy. Osteocytes have interconnecting dendritic networks and are a model to investigate its mechanism. We have demonstrated, in primary murine osteocytes with photoactivatable mitochondria (PhAM)floxed and in MLO-Y4 cells, mitochondrial transfer in the dendritic networks visualized by high-resolution confocal imaging. Normal osteocytes transferred mitochondria to adjacent metabolically stressed osteocytes and restored their metabolic function. The coordinated movement and transfer of mitochondria within the dendritic network rely on contact between the endoplasmic reticulum (ER) and mitochondria. Mitofusin 2 (Mfn2), a GTPase that tethers ER to mitochondria, predominantly mediates the transfer. A decline in Mfn2 expression with age occurs concomitantly with both impaired mitochondrial distribution and transfer in the osteocyte dendritic network. These data show a previously unknown function of ER-mitochondrial contact in mediating mitochondrial transfer and provide a mechanism to explain the homeostasis of osteocytes.الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::946388371b7d53791e0872dd9012c271Test
https://doi.org/10.1126/sciadv.aaw7215Test -
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المؤلفون: Isotta Lorenzi, Luca Scorrano
المصدر: Science Signaling. 12
مصطلحات موضوعية: 0303 health sciences, education.field_of_study, urogenital system, Endoplasmic reticulum, 030305 genetics & heredity, MFN2, Genetic disorder, Autosomal dominant polycystic kidney disease, Cell Biology, Mitochondrion, Biology, medicine.disease, Biochemistry, Cell biology, 03 medical and health sciences, Mitofusin-2, Polycystin 2, medicine, Polycystic kidney disease, education, Molecular Biology, 030304 developmental biology
الوصف: Mitofusin 2 (MFN2) tethers mitochondria to the endoplasmic reticulum (ER). In the 7 May 2019 issue of Science Signaling, Kuo et al. report that polycystin 2 (PC2), encoded by a gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), contributes to cystogenesis by affecting MFN2, thus extending the role of mitochondria-ER contact sites to a common genetic disorder.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2fecb19f99309bb0c8f207a7018123bbTest
https://doi.org/10.1126/scisignal.aaw6996Test -
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المؤلفون: Jeffrey L. Falcone, David L. Kaplan, Fernanda O. Lemos, Allison L. Brill, Ivana Y. Kuo, Jason Y. Jiang, Ke Dong, Darren P. Wallace, Yiqiang Cai, Aldebaran M. Hofer, Barbara E. Ehrlich, Erica P. Kimmerling
المصدر: Science Signaling. 12
مصطلحات موضوعية: endocrine system, 0303 health sciences, Gene knockdown, education.field_of_study, Chemistry, Endoplasmic reticulum, MFN2, Cell Biology, Mitochondrion, Biochemistry, Cell biology, 03 medical and health sciences, Mitofusin-2, 0302 clinical medicine, Polycystin 2, Mitochondrial biogenesis, 030220 oncology & carcinogenesis, Signal transduction, education, Molecular Biology, 030304 developmental biology
الوصف: Mitochondria and the endoplasmic reticulum (ER) have an intimate functional relationship due to tethering proteins that bring their membranes in close (~30 nm) apposition. One function of this interorganellar junction is to increase the efficiency of Ca2+ transfer into mitochondria, thus stimulating mitochondrial respiration. Here, we showed that the ER cation-permeant channel polycystin 2 (PC2) functions to reduce mitochondria-ER contacts. In cell culture models, PC2 knockdown led to a 50% increase in mitofusin 2 (MFN2) expression, an outer mitochondrial membrane GTPase. Live-cell super-resolution and electron microscopy analyses revealed enhanced MFN2-dependent tethering between the ER and mitochondria in PC2 knockdown cells. PC2 knockdown also led to increased ER-mediated mitochondrial Ca2+ signaling, bioenergetic activation, and mitochondrial density. Mutation or deletion of the gene encoding for PC2 results in autosomal dominant polycystic kidney disease (ADPKD), a condition characterized by numerous fluid-filled cysts. In cell culture models and mice with kidney-specific PC2 knockout, knockdown of MFN2 rescued defective mitochondrial Ca2+ transfer and diminished cell proliferation in kidney cysts. Consistent with these results, cyst-lining epithelial cells from human ADPKD kidneys had a twofold increase in mitochondria and MFN2 expression. Our data suggest that PC2 normally serves to limit key mitochondrial proteins at the ER-mitochondrial interface and acts as a checkpoint for mitochondrial biogenesis and bioenergetics. Loss of this regulation may contribute to the increased oxidative metabolism and aberrant cell proliferation typical of kidney cysts in ADPKD.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::893f4ab0ff8b1ba21ad50cb26110f2afTest
https://doi.org/10.1126/scisignal.aat7397Test -
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المؤلفون: L. Bryan Ray
المصدر: Science Signaling. 6
مصطلحات موضوعية: Chemistry, Depolarization, PINK1, Cell Biology, Mitochondrion, Biochemistry, Parkin, nervous system diseases, Cell biology, Mitofusin-2, Mitophagy, Receptor, Protein kinase A, Molecular Biology
الوصف: Damaged mitochondria are removed from cells in a process known as mitophagy. Failure of this quality-control mechanism contributes to Parkinson’s disease. When damaged mitochondria lose membrane depolarization, the protein kinase, PINK1, accumulates on the mitochondrial surface, recruits Parkin, and promotes mitophagy. Chen and Dorn describe another component of this process, mitofusin 2, which appears to function as the receptor for Parkin on the surface of damaged mitochondria. Y. Chen, G. W. Dorn II, PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340 , 471–475 (2013). [Abstract] [Full Text]
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::02fa0bd52610d0c6516be7969b6ca2e5Test
https://doi.org/10.1126/scisignal.2004274Test -
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المؤلفون: Takumi Koshiba, Yusuke Yanagi, Shun Ichiro Kawabata, Kai Yasukawa
المصدر: Science Signaling. 4
مصطلحات موضوعية: Carbonyl Cyanide m-Chlorophenyl Hydrazone, Blotting, Western, MFN2, Gene Expression, Mitochondrion, Biology, Sendai virus, Biochemistry, GTP Phosphohydrolases, Mice, Mitofusin-2, Animals, Humans, MFN1, Encephalomyocarditis virus, Molecular Biology, Cells, Cultured, Adaptor Proteins, Signal Transducing, Membrane Potential, Mitochondrial, Mice, Knockout, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, Uncoupling Agents, Signal transducing adaptor protein, Interferon-beta, Cell Biology, Fibroblasts, Embryo, Mammalian, Molecular biology, Cell biology, HEK293 Cells, Microscopy, Fluorescence, mitochondrial fusion, Host-Pathogen Interactions, Signal transduction, RNA Helicases, Signal Transduction, Interferon regulatory factors
الوصف: Mitochondria, dynamic organelles that undergo cycles of fusion and fission, are the powerhouses of eukaryotic cells and are also involved in cellular innate antiviral immunity in mammals. Mitochondrial antiviral immunity depends on activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway and the participation of a mitochondrial outer membrane adaptor protein called MAVS (mitochondrial antiviral signaling). We found that cells that lack the ability to undergo mitochondrial fusion as a result of targeted deletion of both mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) exhibited impaired induction of interferons and proinflammatory cytokines in response to viral infection, resulting in increased viral replication. In contrast, cells with null mutations in either Mfn1 or Mfn2 retained their RLR-induced antiviral responses. We also found that a reduced mitochondrial membrane potential (ΔΨ(m)) correlated with the reduced antiviral response. The dissipation in ΔΨ(m) did not affect the activation of the transcription factor interferon regulatory factor 3 downstream of MAVS, which suggests that ΔΨ(m) and MAVS are coupled at the same stage in the RLR signaling pathway. Our results provide evidence that the physiological function of mitochondria plays a key role in innate antiviral immunity.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8dfb2c0fdd37813c440b116768aa0a58Test
https://doi.org/10.1126/scisignal.2001147Test -
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المؤلفون: Hiroyuki Oshiumi, Shun Ichiro Kawabata, Yusuke Yanagi, Takumi Koshiba, Naotada Ishihara, Tsukasa Seya, Makoto Takeda, Kai Yasukawa
المصدر: Science Signaling. 2
مصطلحات موضوعية: Blotting, Western, MFN2, Protein Serine-Threonine Kinases, Biology, Transfection, Models, Biological, Biochemistry, Cell Line, GTP Phosphohydrolases, Mitochondrial Proteins, Mice, Mitofusin-2, RNA interference, Animals, Humans, Immunoprecipitation, Molecular Biology, Transcription factor, Cells, Cultured, Adaptor Proteins, Signal Transducing, Mice, Knockout, TNF Receptor-Associated Factor 6, NF-kappa B, Membrane Proteins, Signal transducing adaptor protein, Cell Biology, Fibroblasts, Mitochondria, Cell biology, mitochondrial fusion, Viral replication, Measles virus, Host-Pathogen Interactions, Chromatography, Gel, Interferon Regulatory Factor-3, RNA Interference, HeLa Cells, Protein Binding, Interferon regulatory factors
الوصف: The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-beta and thereby decreased viral replication. Structure-function analysis revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. Our results suggest that Mfn2 acts as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc1a8b74a819eef82f29326c88aa12b7Test
https://doi.org/10.1126/scisignal.2000287Test -
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المؤلفون: Stella M. Hurtley
المصدر: Science. 317:1010-1010
مصطلحات موضوعية: Genetics, Cerebellum, Mitochondrial DNA, Multidisciplinary, MFN2, Biology, Mitochondrion, Respiratory enzyme, Cell biology, Mitofusin-2, medicine.anatomical_structure, mitochondrial fusion, Organelle, medicine
الوصف: NEUROSCIENCE Mitochondria—the microscopic powerhouses of the cell—contain their own vestigial genome (mtDNA), and each cell needs a collection of healthy organelles to survive. Mitochondria are highly dynamic and undergo both fission and fusion. They produce adenosine 5'-triphosphate by transferring electrons from organic substrates through a series of respiratory enzyme complexes to molecular oxygen. Chen et al. examined the function of the mitochondrial fusion protein mitofusin 2; mutations in the gene Mfn2 have been linked to the peripheral neuropathy Charcot-Marie-Tooth type 2A, in which the very long motor and sensory neurons of the lower leg die. They generated mice that lacked Mfn2 specifically in the cerebellum and found that the mutant mice suffered cerebellar degeneration. Mitochondrial distribution, morphology, and function were all compromised in Mfn2-deficient cells, and many mitochondria appeared to have lost their normal complement of mtDNA. The authors propose that a dynamic fusion capacity is required to maintain the genetic where-withal for each mitochondrion to synthesize adequate supplies of respiratory enzymes. Furthermore, it seems that the Purkinje cells of the cerebellum are particularly sensitive to changes in the distribution and respiratory activity of their mitochondria, perhaps as a consequence of their extensive ramifications. — SMH Cell 130 , 548 (2007).
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::dd45bc375a52382db3b189b924bdeb85Test
https://doi.org/10.1126/science.317.5841.1010aTest