Acquired expression of mutant Mitofusin 2 causes progressive neurodegeneration and abnormal behavior
Kaori IshikawaSatoshi YamamotoSatoko HattoriNaoya NishimuraTakayuki MitoHirokazu MatsumotoTsuyoshi MiyakawaKazuto Nakada
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Abstract:
Neurons have high plasticity in developmental and juvenile stages that decreases in adulthood. Mitochondrial dynamics are highly important in neurons to maintain normal function. To compare dependency on mitochondrial dynamics in juvenile and adult stages, we generated a mouse model capable of selective timing of the expression of a mutant of the mitochondrial fusion factor Mitofusin 2 (MFN2). Mutant expression in the juvenile stage had lethal effects. Contrastingly, abnormalities did not manifest until 150 d after mutant expression during adulthood. After this silent 150 d period, progressive neurodegeneration, abnormal behaviors, and learning and memory deficits similar to those seen in human neurodegenerative diseases were observed. This indicates that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. Our findings highlight the need to consider the timing of disease onset in mimicking human neurodegenerative diseases. SIGNIFICANCE STATEMENT To compare the dependency on mitochondrial dynamics in neurons in juvenile and adult stages, we generated a mouse model expressing a mutant of the mitochondrial fusion factor MFN2 in an arbitrary timing. Juvenile expression of the mutant showed acute and severe phenotypes and had lethal effects; however, post-adult expression induced delayed but progressive phenotypes resembling those found in human neurodegenerative diseases. Our results indicate that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. This strongly suggests that the timing of expression should be considered when establishing an animal model that closely resembles human neurodegenerative diseases.Keywords:
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Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.
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ABSTRACT Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin‐related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non‐neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.
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Mitochondrial dynamics has always been the focus of research, which is not only related to mitochondria themselves, but also is the key to maintaining normal cellular metabolism. Mitochondrial fission and fusion are two important mitochondrial events, in which a series of proteins are involved. Based on previous studies, we have come to the conclusion that mitochondrial fusion proteins not only play an important role in mitochondrial fusion, but also are vital to the changes during apoptosis. This article mainly focuses on Mfn1, Mfn2 and OPA1, and discusses their effects on mitochondrial fusion and apoptosis.
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In recent years, the dynamic nature of mitochondria has been discovered to be critical for their function. Here we discuss the molecular basis of mitochondrial fusion, its protective role in neurodegeneration, and its importance in cellular function. The mitofusins Mfn1 and Mfn2, GTPases localized to the outer membrane, mediate outer‐membrane fusion. OPA1, a GTPase associated with the inner membrane, mediates subsequent inner‐membrane fusion. Mutations in Mfn2 or OPA1 cause neurodegenerative diseases. Mouse models with defects in mitochondrial fusion genes have provided important avenues for understanding how fusion maintains mitochondrial physiology and neuronal function. Mitochondrial fusion enables content mixing within a mitochondrial population, thereby preventing permanent loss of essential components. Cells with reduced mitochondrial fusion, as a consequence, show a subpopulation of mitochondria that lack mtDNA nucleoids. Such mtDNA defects lead to respiration‐deficient mitochondria, and their accumulation in neurons leads to impaired outgrowth of cellular processes and ultimately neurodegeneration.
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Mitochondria are central organelles in metabolism, signal transduction, and programmed cell death. To meet their diverse functional demands, their shape is strictly regulated by a growing family of proteins that impinge on fission and fusion of the organelle. Mitochondrial fusion depends on Mitofusin (Mfn) 1 and 2, two integral outer-membrane proteins. Although MFN1 seems primarily involved in the regulation of the docking and fusion of the organelle, mounting evidence is implicating MFN2 in multiple signaling pathways not restricted to the regulation of mitochondrial shape. Here we review data supporting a role for this mitochondria-shaping protein beyond fusion, in regulating mitochondrial metabolism, apoptosis, shape of other organelles, and even progression through cell cycle. In conclusion, MFN2 appears a multifunctional protein whose biologic function is not restricted to the regulation of mitochondrial shape.
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Background
Cardiovascular disease is the leading cause of morbidity and mortality among diabetic patients. Diabetic cardiomyopathy is closely linked to mitochondrial dysfunction, however the pathophysiological mechanisms responsible are not known. Maintenance of mitochondrial function relies on the balance between fusion and fission events. The fusion protein mitofusin-2 (Mfn2) has been implicated in the pathogenesis of diabetes. Alongside fusion, Mfn2 is widely believed to function as a molecular tether, binding mitochondria to the sarcoplasmic reticulum (SR) to form specialised Ca2+microdomains. Nonetheless, the role of Mfn2 in the heart is poorly characterised. Therefore, the aim of this study was to investigate changes to cardiac mitochondrial protein expression and function in diabetes with a particular focus upon the fusion/fission axis.Methods and results
Protein expression levels were measured in control and streptozotocin-treated (STZ) Wistar rat heart using Western Blot. Mitochondrial OXPHOS function was assessed using enzyme activity assays. Lastly, changes to the mitochondrial proteome were investigated using Mass Spectrometry (MS). Western Blot showed a significant increase in Mfn1 and Mfn2 expression levels in STZ compared to controls with no change to the fission protein Drp1. Enzymatic assays revealed that mitochondrial function was altered in the STZ rat heart compared to control. Lastly, MS identified 1437 proteins, of which there was an upregulation of proteins involved in beta oxidation in the STZ compared to controls. In contrast, there was a downregulation of proteins associated with OXPHOS in the STZ suggesting mitochondrial dysfunction that corroborates the functional data.Conclusion
These data suggest that mitochondrial dysfunction may be linked to an imbalance of the mitochondrial fusion/fission axis in the diabetic heart. Future work will focus on the 3-D reconstruction of the mitochondrial networks using electron microscopy to determine whether changes to mitochondrial function are linked to structural alterations. These studies will enhance our understanding of the pathogenesis of cardiac mitochondrial dysfunction in diabetes, with the hope to elucidate potential targets for therapeutic intervention.MFN2
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Mitochondria form a dynamic network within the cell as a result of balanced fusion and fission. Despite the established role of mitofusins (MFN1 and MFN2) in mitochondrial fusion, only MFN2 has been associated with metabolic and neurodegenerative diseases, which suggests that MFN2 is needed to maintain mitochondrial energy metabolism. The molecular basis for the mitochondrial dysfunction encountered in the absence of MFN2 is not understood. Here we show that loss of MFN2 leads to impaired mitochondrial respiration and reduced ATP production, and that this defective oxidative phosphorylation process unexpectedly originates from a depletion of the mitochondrial coenzyme Q pool. Our study unravels an unexpected and novel role for MFN2 in maintenance of the terpenoid biosynthesis pathway, which is necessary for mitochondrial coenzyme Q biosynthesis. The reduced respiratory chain function in cells lacking MFN2 can be partially rescued by coenzyme Q10 supplementation, which suggests a possible therapeutic strategy for patients with diseases caused by mutations in the Mfn2 gene.
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Muscle from obese subjects or from type 2 diabetic patients show mitochondrial dysfunction, and this may participate in the insulin resistance in those conditions. The mechanisms involved in mitochondrial dysfunction are not completely understood. Dynamic mitochondrial filaments or networks form by mitochondrial fusion and fission events. There is substantial evidence that proteins participating in mitochondrial fusion or fission also have a role in metabolism. Thus, mitofusin-2 (Mfn2) a mitochondrial fusion protein, stimulates respiration, substrate oxidation and OXPHOS subunits expression. In this regard, muscle from obese subjects, or from type 2 diabetic patients, show a reduced expression of Mfn2 and, amelioration of insulin sensitivity by bariatric surgery is associated with an increased Mfn2 expression in muscle. Here, we propose the hypothesis that mitochondrial dynamics proteins play a role in mitochondrial dysfunction in obesity or in type 2 diabetes and that it may also participate in the development of insulin resistance.
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