The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
David C Chan - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial dynamics is a distinguishing feature of skeletal muscle fiber types and regulates organellar compartmentalization
Cell Metabolism, 2015Co-Authors: Prashant Mishra, Grigor Varuzhanyan, Anh H Pham, David C ChanAbstract:Skeletal muscle fibers differentiate into specific fiber types with distinct metabolic properties determined by their reliance on oxidative phosphorylation (OXPHOS). Using in vivo approaches, we find that OXPHOS-dependent fibers, compared to glycolytic fibers, contain elongated mitochondrial networks with higher fusion rates that are dependent on the mitofusins Mfn1 and MFN2. Switching of a glycolytic fiber to an oxidative IIA type is associated with elongation of mitochondria, suggesting that mitochondrial fusion is linked to metabolic state. Furthermore, we reveal that mitochondrial proteins are compartmentalized to discrete domains centered around their nuclei of origin. The domain dimensions are dependent on fiber type and are regulated by the mitochondrial dynamics proteins Mfn1, MFN2, and Mff. Our results indicate that mitochondrial dynamics is tailored to fiber type physiology and provides a rationale for the segmental defects characteristic of aged and diseased muscle fibers.
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loss of MFN2 results in progressive retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit
Human Molecular Genetics, 2012Co-Authors: Anh H Pham, Shuxia Meng, Quynh N Chu, David C ChanAbstract:Mitochondria continually undergo fusion and fission, and these dynamic processes play a major role in regulating mitochondrial function. Studies of several genes associated with familial Parkinson's disease (PD) have implicated aberrant mitochondrial dynamics in the disease pathology, but the importance of these processes in dopaminergic neurons remains poorly understood. Because the mitofusins Mfn1 and MFN2 are essential for mitochondrial fusion, we deleted these genes from a subset of dopaminergic neurons in mice. Loss of MFN2 results in a movement defect characterized by reduced activity and rearing. In open field tests, MFN2 mutants show severe, age-dependent motor deficits that can be rescued with L-3,4 dihydroxyphenylalanine. These motor deficits are preceded by the loss of dopaminergic terminals in the striatum. However, the loss of dopaminergic neurons in the midbrain occurs weeks after the onset of these motor and striatal deficits, suggesting a retrograde mode of neurodegeneration. In our conditional knockout strategy, we incorporated a mitochondrially targeted fluorescent reporter to facilitate tracking of mitochondria in the affected neurons. Using an organotypic slice culture system, we detected fragmented mitochondria in the soma and proximal processes of these neurons. In addition, we found markedly reduced mitochondrial mass and transport, which may contribute to the neuronal loss. These effects are specific for MFN2, as the loss of Mfn1 yielded no corresponding defects in the nigrostriatal circuit. Our findings indicate that perturbations of mitochondrial dynamics can cause nigrostriatal defects and may be a risk factor for the neurodegeneration in PD.
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complementation between mouse mfn1 and MFN2 protects mitochondrial fusion defects caused by cmt2a disease mutations
Journal of Cell Biology, 2007Co-Authors: Scott A. Detmer, David C ChanAbstract:MFN2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, MFN2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why MFN2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of MFN2. In this study, we show that homooligomeric complexes formed by many MFN2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant MFN2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type MFN2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–MFN2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.
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disruption of fusion results in mitochondrial heterogeneity and dysfunction
Journal of Biological Chemistry, 2005Co-Authors: Hsiuchen Chen, Anne Chomyn, David C ChanAbstract:Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or MFN2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and MFN2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzo yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.
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mitofusins mfn1 and MFN2 coordinately regulate mitochondrial fusion and are essential for embryonic development
Journal of Cell Biology, 2003Co-Authors: Hsiuchen Chen, Scott A. Detmer, Andrew J Ewald, Erik E Griffin, Scott E Fraser, David C ChanAbstract:Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and MFN2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or MFN2 die in midgestation. However, whereas MFN2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or MFN2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and MFN2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and MFN2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.
Antonio Zorzano - One of the best experts on this subject based on the ideXlab platform.
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macrophage mitochondrial MFN2 mitofusin 2 links immune stress and immune response through reactive oxygen species ros production
Autophagy, 2020Co-Authors: Jorge Lloberas, Antonio Zorzano, Maria Isabel Hernandezalvarez, Juan Pablo Munoz, Perejoan Cardona, Antonio CeladaAbstract:MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. The lack of MFN2 in macrophages causes an impaired response in a model of non-septic inflammation in mice, as well as a failure in protection from Listeria, Mycobacterium tuberculosis or LPS endotoxemia. These results reveal an unexpected role of MFN2 to ROS production in macrophages affecting natural and acquired immunity and the immune response.
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MFN2 is critical for brown adipose tissue thermogenic function
The EMBO Journal, 2017Co-Authors: Marie Boutant, Antonio Zorzano, Sameer S Kulkarni, Magali Joffraud, Joanna Ratajczak, Miriam Valeraalberni, Roy CombeAbstract:Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine-tune cellular bioenergetics. Defective mitofusin 2 (MFN2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin-resistant states. Interestingly, MFN2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose-specific MFN2 knockout (MFN2-adKO) mice, we demonstrate that MFN2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, MFN2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, MFN2-adKO mice were protected from high-fat diet-induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that MFN2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole-body energy homeostasis.
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the charcot marie tooth type 2a gene product MFN2 up regulates fuel oxidation through expression of oxphos system
Human Molecular Genetics, 2005Co-Authors: Sara Pich, Marc Liesa, Daniel Bach, Paz Briones, Marta Camps, Xavier Testar, Manuel Palacin, Antonio ZorzanoAbstract:Mitofusin-2 (MFN2) is a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells and mutations in the MFN2 gene cause Charcot-Marie-Tooth neuropathy type 2A. Here, we show that MFN2 loss-of-function inhibits pyruvate, glucose and fatty acid oxidation and reduces mitochondrial membrane potential, whereas MFN2 gain-of-function increases glucose oxidation and mitochondrial membrane potential. As to the mechanisms involved, we have found that MFN2 loss-of-function represses nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas MFN2 overexpression induced the subunits of complexes I, IV and V. Obesity-induced MFN2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III and V. In addition, the effect of MFN2 overexpression on mitochondrial metabolism was mimicked by a truncated MFN2 mutant that is inactive as a mitochondrial fusion protein. Our results indicate that MFN2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein.
Suzanne Hoppins - One of the best experts on this subject based on the ideXlab platform.
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identification of a mitofusin specificity region that confers unique activities to mfn1 and MFN2
Molecular Biology of the Cell, 2019Co-Authors: Stephanie R Sloat, B N Whitley, E A Engelhart, Suzanne HoppinsAbstract:Mitochondrial structure can be maintained at steady state or modified in response to changes in cellular physiology. This is achieved by the coordinated regulation of dynamic properties including mitochondrial fusion, division, and transport. Disease states, including neurodegeneration, are associated with defects in these processes. In vertebrates, two mitofusin paralogues, Mfn1 and MFN2, are required for efficient mitochondrial fusion. The mitofusins share a high degree of homology and have very similar domain architecture, including an amino terminal GTPase domain and two extended helical bundles that are connected by flexible regions. Mfn1 and MFN2 are nonredundant and are both required for mitochondrial outer membrane fusion. However, the molecular features that make these proteins functionally distinct are poorly defined. By engineering chimeric proteins composed of Mfn1 and MFN2, we discovered a region that contributes to isoform-specific function (mitofusin isoform-specific region [MISR]). MISR confers unique fusion activity and mitofusin-specific nucleotide-dependent assembly properties. We propose that MISR functions in higher-order oligomerization either directly, as an interaction interface, or indirectly through conformational changes.
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identification of a mitofusin specificity region that confers unique activities to mfn1 and MFN2
bioRxiv, 2019Co-Authors: Stephanie R Sloat, B N Whitley, E A Engelhart, Suzanne HoppinsAbstract:ABSTRACT Mitochondrial structure can be maintained at steady state or modified in response to changes in cellular physiology. This is achieved by the coordinated regulation of dynamic properties including mitochondrial fusion, division and transport. Disease states, including neurodegeneration, are associated with defects in these processes. In vertebrates, two Mitofusin paralogs, Mfn1 and MFN2, are required for efficient mitochondrial fusion. The Mitofusins share a high degree of homology and have very similar domain architecture, including an amino terminal GTPase domain and two extended helical bundles that are connected by flexible regions. Mfn1 and MFN2 are non-redundant and are both required for mitochondrial outer membrane fusion. However, the molecular features that make these proteins functionally distinct are poorly defined. By engineering chimeric proteins composed of Mfn1 and MFN2, we discovered a region that contributes to isoform-specific function (Mitofusin Isoform Specific Region – MISR). MISR confers unique fusion activity and Mitofusin specific nucleotide-dependent assembly properties. We propose that MISR functions in higher order oligomerization either directly, as an interaction interface, or indirectly through conformational changes.
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a catalytic domain variant of mitofusin requiring a wildtype paralog for function uncouples mitochondrial outer membrane tethering and fusion
Journal of Biological Chemistry, 2019Co-Authors: Emily A Engelhart, Suzanne HoppinsAbstract:Mitofusins (Mfns) are dynamin-related GTPases that mediate mitochondrial outer-membrane fusion, a process that is required for mitochondrial and cellular health. In Mfn1 and MFN2 paralogs, a conserved phenylalanine (Phe-202 (Mfn1) and Phe-223 (MFN2)) located in the GTPase domain on a conserved β strand is part of an aromatic network in the core of this domain. To gain insight into the poorly understood mechanism of Mfn-mediated membrane fusion, here we characterize a Mitofusin mutant variant etiologically linked to Charcot–Marie–Tooth syndrome. From analysis of mitochondrial structure in cells and mitochondrial fusion in vitro, we found that conversion of Phe-202 to leucine in either Mfn1 or MFN2 diminishes the fusion activity of heterotypic complexes with both Mfn1 and MFN2 and abolishes fusion activity of homotypic complexes. Using coimmunoprecipitation and native gel analysis, we further dissect the steps of mitochondrial fusion and demonstrate that the mutant variant has normal tethering activity but impaired higher-order nucleotide-dependent assembly. The defective coupling of tethering to membrane fusion observed here suggests that nucleotide-dependent self-assembly of Mitofusin is required after tethering to promote membrane fusion.
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the soluble form of bax regulates mitochondrial fusion via MFN2 homotypic complexes
Molecular Cell, 2011Co-Authors: Suzanne Hoppins, Megan M Cleland, Richard J Youle, Michael J Mccaffery, Frank Edlich, Soojay Banerjee, Jodi NunnariAbstract:In mammals, fusion of the mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane fusion DRPs using an in vitro mammalian mitochondrial fusion assay. We demonstrate that heterotypic MFN1-MFN2 trans complexes possess greater efficacy in fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the proapoptotic Bcl2 protein, Bax, positively regulates mitochondrial fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles.
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coassembly of mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion
Journal of Cell Biology, 2009Co-Authors: Rachel M Devay, Suzanne Hoppins, Lenin Dominguezramirez, Laura L Lackner, Henning Stahlberg, Jodi NunnariAbstract:Two dynamin-related protein (DRP) families are essential for fusion of the outer and inner mitochondrial membranes, Fzo1 (yeast)/Mfn1/MFN2 (mammals) and Mgm1 (yeast)/Opa1 (mammals), respectively. Fzo1/Mfns possess two medial transmembrane domains, which place their critical GTPase and coiled-coil domains in the cytosol. In contrast, Mgm1/Opa1 are present in cells as long (l) isoforms that are anchored via the N terminus to the inner membrane, and short (s) isoforms were predicted to be soluble in the intermembrane space. We addressed the roles of Mgm1 isoforms and how DRPs function in membrane fusion. Our analysis indicates that in the absence of a membrane, l- and s-Mgm1 both exist as inactive GTPase monomers, but that together in trans they form a functional dimer in a cardiolipin-dependent manner that is the building block for higher-order assemblies.
Gerald W Dorn - One of the best experts on this subject based on the ideXlab platform.
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the tethering function of mitofusin2 controls osteoclast differentiation by modulating the ca2 nfatc1 axis
Journal of Biological Chemistry, 2020Co-Authors: Anna Ballard, Gerald W Dorn, Rong Zeng, Allahdad Zarei, Christine Shao, Linda Cox, Hui Yan, Antonietta Franco, Roberta X FaccioAbstract:Dynamic regulation of the mitochondrial network by mitofusins (MFNs) modulates energy production, cell survival, and many intracellular signaling events, including calcium handling. However, the relative importance of specific mitochondrial functions and their dependence on MFNs vary greatly among cell types. Osteoclasts have many mitochondria, and increased mitochondrial biogenesis and oxidative phosphorylation enhance bone resorption, but little is known about the mitochondrial network or MFNs in osteoclasts. Because expression of each MFN isoform increases with osteoclastogenesis, we conditionally deleted MFN1 and MFN2 (double conditional KO (dcKO)) in murine osteoclast precursors, finding that this increased bone mass in young female mice and abolished osteoclast precursor differentiation into mature osteoclasts in vitro. Defective osteoclastogenesis was reversed by overexpression of MFN2 but not MFN1; therefore, we generated mice lacking only MFN2 in osteoclasts. MFN2-deficient female mice had increased bone mass at 1 year and resistance to Receptor Activator of NF-κB Ligand (RANKL)-induced osteolysis at 8 weeks. To explore whether MFN-mediated tethering or mitophagy is important for osteoclastogenesis, we overexpressed MFN2 variants defective in either function in dcKO precursors and found that, although mitophagy was dispensable for differentiation, tethering was required. Because the master osteoclastogenic transcriptional regulator nuclear factor of activated T cells 1 (NFATc1) is calcium-regulated, we assessed calcium release from the endoplasmic reticulum and store-operated calcium entry and found that the latter was blunted in dcKO cells. Restored osteoclast differentiation by expression of intact MFN2 or the mitophagy-defective variant was associated with normalization of store-operated calcium entry and NFATc1 levels, indicating that MFN2 controls mitochondrion–endoplasmic reticulum tethering in osteoclasts.
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abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence
Cell Metabolism, 2017Co-Authors: Moshi Song, Antonietta Franco, Julie Fleischer, Lihong Zhang, Gerald W DornAbstract:Summary Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/MFN2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/MFN2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence.
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functional implications of mitofusin 2 mediated mitochondrial sr tethering
Journal of Molecular and Cellular Cardiology, 2015Co-Authors: Gerald W Dorn, Moshi Song, Kenneth WalshAbstract:Cardiomyocyte mitochondria have an intimate physical and functional relationship with sarcoplasmic reticulum (SR). Under normal conditions mitochondrial ATP is essential to power SR calcium cycling that drives phasic contraction/relaxation, and changes in SR calcium release are sensed by mitochondria and used to modulate oxidative phosphorylation according to metabolic need. When perturbed, mitochondrial-SR calcium crosstalk can evoke programmed cell death. Physical proximity and functional interplay between mitochondria and SR are maintained in part through tethering of these two organelles by the membrane protein mitofusin 2 (MFN2). Here we review and discuss findings from our two laboratories that derive from genetic manipulation of MFN2 and closely related Mfn1 in mouse hearts and other experimental systems. By comparing the findings of our two independent research efforts we arrive at several conclusions that appear to be strongly supported, and describe a few areas of incomplete understanding that will require further study. In so doing we hope to clarify some misconceptions regarding the many varied roles of MFN2 as both physical trans-organelle tether and mitochondrial fusion protein. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease."
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mitochondrial genome linearization is a causative factor for cardiomyopathy in mice and drosophila
Antioxidants & Redox Signaling, 2014Co-Authors: Yun Chen, Megan Sparks, Poonam Bhandari, Scot J Matkovich, Gerald W DornAbstract:Abstract Aims: Mitofusin (Mfn)2 redundantly promotes mitochondrial outer membrane tethering and organelle fusion with Mfn1, and uniquely functions as the mitochondrial receptor for Parkin during PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy. Selective deletion of MFN2 with retention of Mfn1 preserves mitochondrial fusion while rendering damaged mitochondria resistant to normal quality control culling mechanisms. Consequently, neuron and cardiomyocyte-specific MFN2 gene ablation is associated with accumulation of damaged mitochondria and organ dysfunction. Here, we determined how mitochondrial DNA (mtDNA) damage contributes to cardiomyopathy in MFN2-deficient hearts. Results: RNA sequencing of MFN2-deficient hearts revealed increased expression of some nuclear-encoded mitochondrial genes, but mitochondrial-encoded transcripts were not upregulated in parallel and mtDNA content was decreased. Ultra-deep sequencing of mtDNA showed no increase in single nucleotide mutations, but copy number ...
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two rare human mitofusin 2 mutations alter mitochondrial dynamics and induce retinal and cardiac pathology in drosophila
PLOS ONE, 2012Co-Authors: William H Eschenbacher, Yun Chen, Moshi Song, Casey C Jowdy, Poonam Bhandari, Peter Zhao, John T Engelhard, Gerald W DornAbstract:Mitochondrial fusion is essential to organelle homeostasis and organ health. Inexplicably, loss of function mutations of mitofusin 2 (MFN2) specifically affect neurological tissue, causing Charcot Marie Tooth syndrome (CMT) and atypical optic atrophy. As CMT-linked MFN2 mutations are predominantly within the GTPase domain, we postulated that MFN2 mutations in other functional domains might affect non-neurological tissues. Here, we defined in vitro and in vivo consequences of rare human mutations in the poorly characterized MFN2 HR1 domain. Human exome sequencing data identified 4 rare non-synonymous MFN2 HR1 domain mutations, two bioinformatically predicted as damaging. Recombinant expression of these (MFN2 M393I and R400Q) in MFN2-null murine embryonic fibroblasts (MEFs) revealed incomplete rescue of characteristic mitochondrial fragmentation, compared to wild-type human MFN2 (hMFN2); MFN2 400Q uniquely induced mitochondrial fragmentation in normal MEFs. To compare MFN2 mutation effects in neurological and non-neurological tissues in vivo, hMFN2 and the two mutants were expressed in Drosophila eyes or heart tubes made deficient in endogenous fly mitofusin (dMfn) through organ-specific RNAi expression. The two mutants induced similar Drosophila eye phenotypes: small eyes and an inability to rescue the eye pathology induced by suppression of dMfn. In contrast, MFN2 400Q induced more severe cardiomyocyte mitochondrial fragmentation and cardiac phenotypes than MFN2 393I, including heart tube dilation, depressed fractional shortening, and progressively impaired negative geotaxis. These data reveal a central functional role for MFN2 HR1 domains, describe organ-specific effects of two MFN2 HR1 mutations, and strongly support prospective studies of MFN2 400Q in heritable human heart disease of unknown genetic etiology.
Maria Isabel Hernandezalvarez - One of the best experts on this subject based on the ideXlab platform.
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macrophage mitochondrial MFN2 mitofusin 2 links immune stress and immune response through reactive oxygen species ros production
Autophagy, 2020Co-Authors: Jorge Lloberas, Antonio Zorzano, Maria Isabel Hernandezalvarez, Juan Pablo Munoz, Perejoan Cardona, Antonio CeladaAbstract:MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. The lack of MFN2 in macrophages causes an impaired response in a model of non-septic inflammation in mice, as well as a failure in protection from Listeria, Mycobacterium tuberculosis or LPS endotoxemia. These results reveal an unexpected role of MFN2 to ROS production in macrophages affecting natural and acquired immunity and the immune response.
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critical reappraisal confirms that mitofusin 2 is an endoplasmic reticulum mitochondria tether
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Deborah Naon, Marta Giacomello, Marta Zaninello, Tatiana Varanita, Francesca Grespi, Sowmya Lakshminaranayan, Annalisa Serafini, Martina Semenzato, Stephanie Herkenne, Maria Isabel HernandezalvarezAbstract:The discovery of the multiple roles of mitochondria–endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER–mitochondria tether. However, this established MFN2 function was recently questioned, calling for a critical re-evaluation of MFN2’s role in ER–mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER–mitochondria juxtaposition was reduced by constitutive or acute MFN2 deletion. Functionally, mitochondrial uptake of Ca2+ released from the ER was reduced following acute MFN2 ablation, as well as in MFN2−/− cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca2+ uptake rate and extent were normal in isolated MFN2−/− liver mitochondria, consistent with the finding that acute or chronic MFN2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, MFN2 stands as a bona fide ER–mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.