Mitofusin 2 as a driver that controls energy metabolism and insulin signaling

Mfn2 pathogenic variants were recently implicated in a very rare autosomal recessive form of msl. Possible treatment for diseases caused by mitofusin 2. Mtc exam 2 questions and study guide quizlet flashcards by. During obesity, the integration and metabolic response in the arc is disrupted by.

Myocardial energy metabolism depends on mitochondria, which must generate. Mitofusin 2 mfn2 is a potent modulator of mitochondrial metabolism with an impact on energy metabolism in muscle, liver, and hypothalamic neurons. Sebastian d1, hernandezalvarez mi, segales j, sorianello e, munoz jp, sala d, waget a, liesa m, paz jc, gopalacharyulu p, oresic m, pich s, burcelin r, palacin m, zorzano a. Zorzano a, hernandezalvarez mi, sebastian d, munoz jp.

Implications of mitochondrial dynamics on neurodegeneration and on. Moreover, the protein kinase kinaseextracellularsignalregulated kinase mapkkerkmek inhibitor pd98059 accelerates insulinmediated myogenesis, whereas the phosphatidylinositol 3kinase pi3k inhibitor ly294002 or blockade of mitochondrial respiration. Few components of the mitochondrial fission machinery are known, even though mitochondrial fission is a complex process of vital importance for cell growth and survival. In fact, proinflammatory cytokines and lipid availability reduced its expression, whereas exercise and increased energy expenditure promoted its upregulation 14, 51. Insulin resistance is a key factor in the development of type 2 diabetes. Skeletal muscle insulin resistance, decreased phosphatidylinositol 3kinase pi3k activation and altered mitochondrial function are hallmarks of type 2. Jul 29, 2016 mitofusin 2 mfn2, one of the mitochondrial dynamic proteins plays a key role in maintaining the integrity of mitochondrial morphology and function. Rats were fed with highfat diets for 8 wk, and then were infected with admitofusin2 mfn2 or empty ad adenovirus or phosphatebuffered saline. Correlations between mitofusin 2 expression in fibroblasts. Multiple symmetric lipomatosis msl is characterized by upperbody lipomatous masses frequently associated with metabolic and neurological signs. The incretin hormone glucagonlike peptide1 glp1 is best known for its incretin effect in restoring glucose homeostasis in diabetics, however, it is now apparent that it has a broader range of physiological effects in the body. Confocal immunofluorescent analysis of hela left and nih3t3 right cells using mitofusin2 d2d10.

Mitofusin 2 as a driver that controls energy metabolism and insulin signaling. For glucosefree conditions, 10 mm dmannitol sigma aldrich, vienna, austria was added instead of glucose. This latter protein controls not only mitochondrial cell energy metabolism but also insulin signaling by limiting ros production and is stringently modulated by several factors. Mitofusin2 regulates the proliferation and function of. Mfn1 is an essential transmembrane gtpase critical to mitochondrial fusion. Importantly, mfn2 controls cell metabolism and insulin signaling by limiting reactive oxygen species production and by modulation of endoplasmic. Butyrate regulates liver mitochondrial function, efficiency. Importantly, mfn2 controls cell metabolism and insulin signaling by limiting reactive oxygen species. Mitofusin2 regulates mitochondrial and endoplasmic reticulum. Mitofusin 2 as a driver that controls energy metabolism and. Insulin stimulates the expression of mfn2 protein, which in turn binds to ras and inhibits the mekdependent signaling pathway. All experiments were performed at room temperature in ambient. Full text mitochondrial dynamic dysfunction as a main. Mfn2 encodes mitofusin2, a mitochondrial fusion protein previously involved in charcotmarietooth neuropathy.

These changes may be explained by a loss of mitochondriaer contacts caused by perturbation of mitofusin 2 function in a specific subset of neurons that ultimately leads to er stressinduced leptin resistance and obesity. Both in vitro and in vivo studies have demonstrated that glp1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic. Jul 15, 2019 the expression levels of the proteins mfn2, procollagens, phosphoprotein 21 wild. The mfn2 proapoptotic effect is independent of its role in mitochondrial fusion but mainly mediated by inhibition of akt signaling and the resultant activation of the mitochondrial apoptotic pathway, as manifested by decreased akt phosphorylation, increased mitochondrial baxbcl2 ratio, cytochrome c release, and activation of caspases9 and. Moreover, the protein kinase kinaseextracellularsignalregulated kinase mapkkerkmek inhibitor pd98059 accelerates insulin mediated myogenesis, whereas the phosphatidylinositol 3kinase pi3k inhibitor ly294002 or blockade of mitochondrial respiration abrogates insulin. Composition, molecular mechanisms, and physiopathological implications. Mitochondria, energy generating organelles, are crucial for most somatic cells 1. Maternal transmission of mitochondrial diseases scielo. Mitofusin 2 as a driver that controls energy metabolism and insulin signaling article pdf available in antioxidants and redox signaling 2212 january 2015 with 527 reads how we measure reads. Mfn2 acts independently of the cytoskeleton, and plays a central role in mitochondrial metabolism. A ubiquitous driver, ac5cgal4, was used to express a gdap1 cdna kickup, ku. Mitofusins, from mitochondria to metabolism sciencedirect.

Eli lilly, indianapolis, in, usa or saline via the portal vein under anesthesia with pentobarbital sodium 50 mgkg. Mfn2 ameliorates cell apoptosis in a cellular model of. In many cells and specially in muscle, mitochondria form elongated filaments or a branched reticulum. Dec 01, 2017 mit 2 as a driver that controls energy metabolism and insulin signaling. Zorzano a1, hernandezalvarez mi, sebastian d, munoz jp. Mitochondrial dynamics is a complex process that impacts on mitochondrial biology. Mar 01, 2017 mitofusin 2 as a driver that controls energy metabolism and insulin signaling zorzano, a hernandezalvarez, m. Researchers suggest that mitochondria cannot fuse properly or move normally within the cell without functional mitofusin 2, which may disrupt the cells energy supply. Importantly, mfn2 controls cell metabolism and insulin signaling by limiting reactive oxygen. Apr 20, 2015 mitofusin 2 as a driver that controls energy metabolism and insulin signaling. My research has elucidated the role of the mitochondrial dynamics protein mitofusin 2 mfn2 in the control of mitochondrial metabolism and its involvement in metabolic disease and aging, by affecting several cellular pathways such as er stress, autophagy and mitophagy sebastian et al. Generally, mitochondrial divisions and fusions are modulated by some proteins such as drp1 and fis1, which are the key fission mediators, as well as by opa1, mfn1 and mfn2, which are fusion mediators in mammals.

Upregulated mir17 regulates hypoxiamediated human pulmonary artery smooth muscle cell proliferation and apoptosis by targeting mitofusin 2. Optimal mitochondrial function is ensured by a qualitycontrol system tightly coupled to fusion and fission. Pdf mitofusin 2 as a driver that controls energy metabolism. All this evidence points to mitofusin 2 as a key regulator of insulin signalling 41. Apoptosis is a programmed cell death that is either. Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction. We have previously shown that mitochondrial activity increases in response to insulin in differentiating muscle cells. Defective insulin signaling and mitochondrial dynamics in diabetic.

In particular, mitochondrial dynamics, through the balance between fusion and fission events, represents a central mechanism for bioenergetic adaptation to metabolic needs of the cell. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy russe hmsnr. Mitochondrial impairment is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Mitofusin 2 mfn2 regulates mitochondrial morphology and signaling and is involved in the development of numerous mitochondrialrelated diseases. In particular, mitochondrial dynamics, through the balance between fusion and fission events, represents a central mechanism for. Crosstalk between hypoxia and insulin signaling via. Mar 16, 2012 mitofusin 2 as a driver that controls energy metabolism and insulin signaling. Role of p110a subunit of pi3kinase in skeletal muscle. Confocal immunofluorescent analysis of hela left and nih3t3 right cells using mitofusin2 d2d10 rabbit mab green.

Cardiovascular diseaseatherosclerosis, obesity and type 2 diabetes are closely associated with chronic inflammation characterized by abnormal cytokine production, increased levels of acutephase reactants and activation of a network of inflammatory signaling pathways. Mitofusin 2 regulates the oocytes development and quality. Antonio zorzano, maria isabel hernandezalvarez, david sebastian, juan pablo munoz pmid 25567790. The expression levels of the proteins mfn2, procollagens, phosphoprotein 21 wild. Mitofusin2 mfn2, one of the mitochondrial dynamic proteins plays a key role in maintaining the integrity of mitochondrial morphology and function. Mitofusin2 overexpression upregulated the expression of insulin pathway related genes in liver of rats. Mitofusin 2 protects hepatocyte mitochondrial function from. Mitofusin 2 as a driver that controls energy metabolism and insulin signaling zorzano, a hernandezalvarez, m. Mit 2 as a driver that controls energy metabolism and insulin signaling.

Recent evidence indicates that proteins participating in mitochondrial dynamics have additional cellular roles. Crosstalk between hypoxia and insulin signaling via phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes running title. A novel phd3hif2irs2 axis regulates hepatic metabolism cullen m. Zorzano a, hernandezalvarez mi, sebastian d and munoz jp. Human biallelic mfn2 mutations induce mitochondrial dysfunction. Realtime imaging of mitochondrial atp dynamics reveals the. Actin d6a8 rabbit mab is used as a loading control. Jul 18, 2014 mitofusin 2 mfn2 is a dynaminlike protein anchored in the outer mitochondrial membrane that plays a crucial role in ensuring optimal mitochondrial morphological homeostasis. Jul 30, 2019 skeletal muscle insulin resistance, decreased phosphatidylinositol 3kinase pi3k activation and altered mitochondrial function are hallmarks of type 2 diabetes.

Mitochondrial fusion process is mediated by mitofusin 1 mfn1 and mitofusin 2 mfn2 proteins in the outer membrane as well as opa1 in the inner mitochondrial membrane. In this connection, mitofusin 2 mfn2 participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Mitochondrial architecture is involved in several functions crucial for cell viability, proliferation, senescence, and signaling. The mitofusin1 d6e2s rabbit mab confirms silencing of mitofusin1 expression, while the. Guidelines for molecular diagnosis of charcotmarietooth disease. Pyruvate acetylcoa tca cycle pdc pdp pdk lipids akhr cg6178 glycogen glucose pyruvate pyrk hex g6pase pepck glys glyp lactatealanine alt ldh insulin signalling zorzano a, hernandezalvarez mi, sebastian d, munoz jp. Mitofusin 2 triggers vascular smooth muscle cell apoptosis. Pleiotropic effects of glp1 and analogs on cell signaling. To efficiently perform these tasks, mitochondria require the close assistance of the endoplasmic reticulum er, as substantiated by the fact that as much as 20% of the mitochondrial surface is in close apposition with the er rizzuto et al. Mitofusin 2 mfn2 links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Pdf mitofusin 2 regulates the oocytes development and. Mitofusin 2 in pomc neurons connects er stress with leptin. Mfn2 encodes mitofusin 2, a mitochondrial fusion protein previously involved in charcotmarietooth neuropathy. Apr 03, 2012 mitochondria are dynamic organelles that play a key role in energy conversion.

Mfn2 encodes mitofusin 2, a membranebound mediator of. Mitochondria are dynamic organelles that play a key role in energy conversion. David sebastian profesor asociado university of barcelona. In addition, mfn2 is subjected to tight regulation. The hypothalamus is a brain region which is key in the control of energy homeostasis. Apr 07, 2015 mitofusin 2 mfn2 is a potent modulator of mitochondrial metabolism with an impact on energy metabolism in muscle, liver, and hypothalamic neurons. Butyrate regulates liver mitochondrial function, efficiency, and. Mitofusin 2 deficiency leads to oxidative stress that. Mitofusin 2 as a driver that controls energy metabolism and insulin. Roles of calcium and mitochondriaassociated membranes in the. Mitofusin2 ameliorates highfat dietinduced insulin. The most prominent metabolic process carried out by mitochondria is oxidative phosphorylation oxphos to generate atp, the universal energy currency. Mitochondrial impairment is hypothesized to contribute to the pathogenesis of insulin resistance.

Mitofusin 2 as a driver that controls energy metabolism. However, it is unknown if mfn2 influences the quality of oocytes in the process of development by modulating mitochondrial function in vitro. Mitofusin 2 is required to maintain mitochondrial coenzyme q levels. Mitofusin 2 expression dominates over mitofusin 1 exclusively in mouse dorsal root ganglia a possible explanation for peripheral nervous system involvement in charcotmarietooth 2a. The novel tailanchored membrane protein mff controls.

Mitofusin mfn proteins regulate the biogenesis and maintenance of the mitochond. Mitofusin2 determines mitochondrial network architecture and. For detecting insulin signaling, at 3 days after burn or sham. Mitofusin 2 mfn2 is a dynaminlike protein anchored in the outer mitochondrial membrane that plays a crucial role in ensuring optimal mitochondrial morphological homeostasis. Mitofusin 2 definition of mitofusin 2 by medical dictionary. Dietinduced obesity is associated with systemic changes, including the induction of er stress in the hypothalmus. It is unclear how mfn2 gene mutations lead to the nerve problems characteristic of type 2a charcotmarietooth disease. A drosophila model of gdap1 function reveals the involvement of. Mitochondria are involved in eukaryotic cell metabolism, calcium homeostasis and signal transduction 2. Mitofusin 2 mfn2 links mitochondrial and endoplasmic.

It has been shown that reduced expression of mfn2 is associated with insulin resistance, but the mechanism is still unclear. We show that mfn2 mitofusin 2, a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, is induced during myogenesis and contributes to the maintenance and operation of the mitochondrial network. Immunohistochemical analysis of paraffinembedded human ovarian carcinoma using mitofusin2 d2d10 rabbit mab in the presence of control peptide left or antigenspecific peptide right. At the same time, the pi3kdependent signaling pathway is boosted, mitochondrial respiration increases and the rate of. Our findings are in line with emerging reports of energy metabolism impairments. Mitochondria also play fundamental roles in multiple cellular processes such as apoptosis, steroid biosynthesis, calcium homeostasis, intermediary metabolism, and cell signaling. Mitofusin 1 and mitofusin 2 function in the context of brain. Roles of the mammalian mitochondrial fission and fusion.