Outer Membrane Fusion Research Articles

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion.

Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration.

The GDP-Bound State of Mitochondrial Mfn1 Induces Membrane Adhesion of Apposing Lipid Vesicles through a Cooperative Binding Mechanism.

Mitochondria are double-membrane organelles that continuously undergo fission and fusion. Outer mitochondrial membrane fusion is mediated by the membrane proteins mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), carrying a GTP hydrolyzing domain (GTPase) and two coiled-coil repeats. The detailed mechanism on how the GTP hydrolysis allows Mfns to approach adjacent membranes into proximity and promote their fusion is currently under debate. Using model membranes built up as giant unilamellar vesicles (GUVs), we show here that Mfn1 promotes membrane adhesion of apposing lipid vesicles. The adhesion forces were sustained by the GDP-bound state of Mfn1 after GTP hydrolysis. In contrast, the incubation with the GDP:AlF, which mimics the GTP transition state, did not induce membrane adhesion. Due to the flexible nature of lipid membranes, the adhesion strength depended on the surface concentration of Mfn1 through a cooperative binding mechanism. We discuss a possible scenario for the outer mitochondrial membrane fusion based on the modulated action of Mfn1.

A Molecular Perspective on Mitochondrial Membrane Fusion: From the Key Players to Oligomerization and Tethering of Mitofusin.

Mitochondria are dynamic organelles characterized by an ultrastructural organization which is essential in maintaining their quality control and ensuring functional efficiency. The complex mitochondrial network is the result of the two ongoing forces of fusion and fission of inner and outer membranes. Understanding the functional details of mitochondrial dynamics is physiologically relevant as perturbations of this delicate equilibrium have critical consequences and involved in several neurological disorders. Molecular actors involved in this process are large GTPases from the dynamin-related protein family. They catalyze nucleotide-dependent membrane remodeling and are widely conserved from bacteria to higher eukaryotes. Although structural characterization of different family members has contributed in understanding molecular mechanisms of mitochondrial dynamics in more detail, the complete structure of some members as well as the precise assembly of functional oligomers remains largely unknown. As increasing structural data become available, the domain modularity across the dynamin superfamily emerged as a foundation for transfering the knowledge towards less characterized members. In this review, we will first provide an overview of the main actors involved in mitochondrial dynamics. We then discuss recent example of computational methodologies for the study of mitofusin oligomers, and present how the usage of integrative modeling in conjunction with biochemical data can be an asset in progressing the still challenging field of membrane dynamics.

Physics-based oligomeric models of the yeast mitofusin Fzo1 at the molecular scale in the context of membrane docking

Tethering and homotypic fusion of mitochondrial outer membranes is mediated by large GTPases of the dynamin-related proteins family called the mitofusins. The yeast mitofusin Fzo1 forms high molecular weight complexes and its assembly during membrane fusion likely involves the formation of high order complexes. Consistent with this possibility, mitofusins form oligomers in both cis (on the same lipid bilayer) and trans to mediate membrane attachment and fusion.Here, we utilize our recent Fzo1 model to investigate and discuss the formation of cis and trans mitofusin oligomers. We have built three distinct cis-assembly Fzo1 models that gave rise to three distinct trans-oligomeric models of mitofusin constructs. Each model involves two main components of mitofusin oligomerization: the GTPase and the trunk domains. The oligomeric models proposed in this study were further assessed for stability and dynamics in a membrane environment using a coarse-grained molecular dynamics (MD) simulation approach. A narrow opening ‘head-to-head’ cis-oligomerization (via the GTPase domain) followed by the antiparallel ‘back-to-back’ trans-associations (via the trunk domain) appears to be in agreement with all of the available experimental data. More broadly, this study opens new possibilities to start exploring cis and trans conformations for Fzo1 and mitofusins in general.

Identification of a mitofusin specificity region that confers unique activities to Mfn1 and Mfn2.

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.

Mitochondrial fusion is required for regulation of mitochondrial DNA replication.

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. To decipher the link between mitochondrial dynamics and mtDNA maintenance, we studied mouse embryonic fibroblasts (MEFs) and mouse cardiomyocytes with disruption of mitochondrial fusion. Super-resolution microscopy revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to nucleoid clustering. Remarkably, fluorescence in situ hybridization (FISH), bromouridine labeling in MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. Furthermore, the profound mtDNA depletion in mouse hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but instead we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.

A catalytic domain variant of mitofusin requiring a wildtype paralog for function uncouples mitochondrial outer-membrane tethering and fusion

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.

Sugar enhances outer membrane fusion in Deinococcus grandis spheroplasts to generate calcium ion-dependent extra-huge cells.

In our previous study, we showed that cell fusion occurred in spheroplasts of Deinococcus grandis at 200 mM calcium chloride in the incubation medium. Extra-huge cells (>0.1 mm in diameter) were observed at this concentration with a low frequency of appearance. In this study, we showed that cell fusion occurred consecutively in D. grandis spheroplasts following an incubation for spheroplast enlargement using medium containing 16.2 mM calcium chloride and 333 mM sucrose. As a result, more extra-huge cells were generated, where cells had maximum diameter of>1 mm. They can be observed with naked eyes in the incubation medium. The giant cells contained multiple cytoplasms covered by the plasma membrane, indicating that the cell fusion occurred only among the outer membranes. Thus, only the outer membrane and the periplasmic space are shared but not the cytoplasm, indicating that genome of each cell remains in its cytoplasm. Our findings indicate that sugar enhances outer membrane fusion in D. grandis spheroplasts to generate calcium ion-dependent extra-huge cells.

Role of mitochondrial fusion in cardiac energy metabolism

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. The goal of our work was to determine the importance of mitochondrial fusion on heart energy homeostasis. To decipher the link between mitochondrial dynamics and mtDNA maintenance and heart energy metabolism, we studied heart conditional knockout mouse and mouse embryonic fibroblasts (MEFs) with disruption of mitochondrial fusion. Super-resolution microscopy analyses revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to clustering and loss of nucleoids. Remarkably, fluorescence in situ hybridization (FISH) in MEFs, bromouridine labeling of MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. The profound mtDNA depletion in hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but, instead, we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.

Identification and characterization of signal peptide of Mitofusin1 (Mfn1)

Mitofusin1 (Mfn1) mediates outer mitochondrial membrane (OMM) fusion in Opisthokonts. The uncharacterized TM comprises to two helices (namely, the TM1 and TM2) connected by an intermembrane loop. Consistent with previous studies, our results from in silico analyses show that all mitofusins lack N terminal-MTS and the TM may act an internal MTS. We have identified a conserved region in TM domain that is responsible for mitochondrial localization of Mfn1/2. Thus, our results suggest the dual function of TM; in OMM anchoring and signaling Mfn1 to mitochondria. Our study illuminates the underlying role of TM for mitochondrial localization of Mfn1 on one hand and also paves a way for the development of tools for in silico prediction of cellular localization of proteins.

Recent insights into the structure and function of Mitofusins in mitochondrial fusion.

Mitochondria undergo frequent fusion and fission events to adapt their morphology to cellular needs. Homotypic docking and fusion of outer mitochondrial membranes are controlled by Mitofusins, a set of large membrane-anchored GTPase proteins belonging to the dynamin superfamily. Mitofusins include, in addition to their GTPase and transmembrane domains, two heptad repeat domains, HR1 and HR2. All four regions are crucial for Mitofusin function, but their precise contribution to mitochondrial docking and fusion events has remained elusive until very recently. In this commentary, we first give an overview of the established strategies employed by various protein machineries distinct from Mitofusins to mediate membrane fusion. We then present recent structure–function data on Mitofusins that provide important novel insights into their mode of action in mitochondrial fusion.

335 - Modulation of dynamic mitochondria by epigenetics in diabetic retinopathy

Introduction Mitochondria are highly dynamic, and they continually fuse and divide. Fusion mixes the contents of two mitochondria, and dilutes injured mitochondrial proteins and DNA. Outer membrane fusion is mediated by fusion proteins, mitofusins (Mfn), and Mfn2 itself is sufficient to modulate mitochondrial metabolism. In the pathogenesis of diabetic retinopathy, mitochondrial structure and DNA are damaged, oxygen consumption is decreased and Mfn2 levels are decreased, and damaged mitochondria accelerates capillary cell apoptosis. Gene expression is also regulated by epigenetic modifications, and these modifications are implicated in the development of diabetic retinopathy. Aim of this study is to investigate the role of epigenetic modifications in the regulation of Mfn2 in diabetic retinopathy. Methods In human retinal endothelial cells, incubated in normal (5mM) or high glucose (20mM) for four days, in the presence/absence of DNA methyltransferase (Dnmt) inhibitors (5-Azacytidine or Dnmt1-siRNA), methylated cytosine (5mC) levels at Mfn2 promoter were quantified by immunecapturing method. Mitochondrial stability was evaluated by measuring membrane permeability, complex-III activity and transcription of mtDNA (cytochrome b, Cytb), and cell apoptosis was quantified by ELISA method using monoclonal antibodies against DNA and histones. Key parameters were evaluated in the retinal microvessels from streptozotocin-induced diabetic mice receiving intravitreal administration of Dnmt1-siRNA. Results Cells exposed to high glucose had increased 5mC levels at Mfn2 promoter. Dnmt inhibition ameliorated increase in 5mC levels, decrease in Mfn2 expression, and protected mitochondrial stability. In the same cells, glucose-induced increase in apoptosis was also ameliorated. Similarly, Dnmt1-siRNA prevented diabetes-induced increase in 5mC at Mfn2 promoter and decrease in its expression. Conclusions DNA methylation of Mfn2 promoter in diabetes, impairs mitochondrial stability, leading to accelerated apoptosis. Thus, targeting Mfn2 DNA methylation could help maintain mitochondrial homeostasis, and halt/retard the development of diabetic retinopathy.

Correction: Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle.

[This corrects the article DOI: 10.1371/journal.pone.0167573.].

Mitochondrial dynamics: overview of molecular mechanisms

Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.

Abstract 5494: Targeting deregulated expression and function of Mitofusin 1 in glioblastoma

Abstract Glioblastoma (GBM) is the most common form of adult primary malignant brain tumor with a poor prognosis. Despite advances in standard treatments, such as surgery, radiation, and adjuvant chemotherapy, outcome remains poor. To further develop effective therapeutic approaches, it is essential to garner a better understanding of GBM progression. Substantial research has shown that GBM's progression is associated with metabolic remodeling, that includes the use of aerobic glycolysis as the main source of energy. Here, we report the novel role of Mitofusin 1 (MFN1), a key regulator of mitochondrial outer membrane fusion in glycolysis. We first established that MFN1 is highly expressed in GBM when compared to its isoform MFN2 using TCGA (The Cancer Genome Atlas) and OncomineTM glioma datasets. Silencing MFN1 using MFN1-shRNA in GBM10 cells showed decreased expression levels of PDK1 and HIF1-alpha as observed in western blotting and RT-PCR analysis. Interestingly, c-myc expression was significantly reduced in the shMFN1 treated GBM 10 cell. In addition, RNASeq analysis conducted on shPDK1 treated GBM-10 cells revealed reduced MFN1 levels. Further silencing of MFN1 showed increased OCR and decreased ECAR using seahorse XFp bio analyzer. Collectively, our preliminary data points to MFN1 as a candidate metabolic oncogene in GBM, and targeting MFN1 will be a novel GBM treatment. Citation Format: Maheedhara Reddy Guda, Swapna Asuthkar, Collin M. Labak, Chase P. Smith, Andrew J. Tsung, Kiran Velpula. Targeting deregulated expression and function of Mitofusin 1 in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5494.

Epigenetics and Mitochondrial Stability in Diabetic Retinopathy

Mitochondria constantly fuse and divide to form a cellular network, and this dynamic fusion-fission controls their function and genome stability. Although both, mitofusin 1 and 2 (Mfn1 and 2) regulate outer mitochondrial membrane fusion, Mfn2 itself is sufficient to modulate mitochondrial metabolism. In diabetes, retinal mitochondria are swollen, respiration is impaired, Mfn2 is decreased and mtDNA is damaged. Diabetes also facilitates epigenetic modifications, altering gene expressions without changing their DNA sequences. This study aims to investigate the role of DNA methylation of Mfn2 in the development of diabetic retinopathy. Methods: Human retinal endothelial cells, incubated in normal (5mmols/L) or high glucose (20mmols/L) for four days, in the presence/absence of DNA methyltransferase (Dnmt) inhibitors (5-Azacytidine or Dnmt1-siRNA), were analyzed for methylated cytosine (5mC) at Mfn2 promoter by immunocapturing method. Mitochondrial integrity was evaluated by membrane permeability, coenzyme Q: cytochrome-c reductase (complex-III) activity, and transcripts of mtDNA-encoded cytochrome b (Cytb). Similar measurements were made in the retinal microvessels from streptozotocin-induced diabetic mice receiving 5-Aza (2.5mg/kg, i.p.) or Dnmt1-siRNA (2µg/2µl, intravitreal). Results: High glucose increased 5mC levels at Mfn2 promoter by over 2 fold, and decreased Mfn2 expression. Dnmt inhibition ameliorated glucose-induced increase in 5mC at Mfn2 and mitochondrial membrane permeability, and decrease in Mfn2 expression, complex III activity and Cytb transcripts. Similarly, in mouse retinal microvessels, inhibition of Dnmt prevented diabetes-induced increase in 5mC at Mfn2 promoter and decrease in Mfn2 expression. Conclusions: In diabetes, epigenetic modifications of Mfn2 promoter impair mitochondrial functional and genomic stability. Thus, targeting DNA methylation could help maintain mitochondrial homeostasis, and halt/retard the development of diabetic retinopathy. Disclosure R. Kowluru: None. M. Mishra: None.

Gene-by-environment interactions that disrupt mitochondrial homeostasis cause neurodegeneration in C. elegans Parkinson\u2019s models

Parkinson’s disease (PD) is a complex multifactorial disorder where environmental factors interact with genetic susceptibility. Accumulating evidence suggests that mitochondria have a central role in the progression of neurodegeneration in sporadic and/or genetic forms of PD. We previously reported that exposure to a secondary metabolite from the soil bacterium, Streptomyces venezuelae, results in age- and dose-dependent dopaminergic (DA) neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. Initial characterization of this environmental factor indicated that neurodegeneration occurs through a combination of oxidative stress, mitochondrial complex I impairment, and proteostatic disruption. Here we present extended evidence to elucidate the interaction between this bacterial metabolite and mitochondrial dysfunction in the development of DA neurodegeneration. We demonstrate that it causes a time-dependent increase in mitochondrial fragmentation through concomitant changes in the gene expression of mitochondrial fission and fusion components. In particular, the outer mitochondrial membrane fission and fusion genes, drp-1 (a dynamin-related GTPase) and fzo-1 (a mitofusin homolog), are up- and down-regulated, respectively. Additionally, eat-3, an inner mitochondrial membrane fusion component, an OPA1 homolog, is also down regulated. These changes are associated with a metabolite-induced decline in mitochondrial membrane potential and enhanced DA neurodegeneration that is dependent on PINK-1 function. Genetic analysis also indicates an association between the cell death pathway and drp-1 following S. ven exposure. Metabolite-induced neurotoxicity can be suppressed by DA-neuron-specific RNAi knockdown of eat-3. AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) ameliorated metabolite- or PINK-1-induced neurotoxicity; however, it enhanced neurotoxicity under normal conditions. These studies underscore the critical role of mitochondrial dynamics in DA neurodegeneration. Moreover, given the largely undefined environmental components of PD etiology, these results highlight a response to an environmental factor that defines distinct mechanisms underlying a potential contributor to the progressive DA neurodegeneration observed in PD.

ROS as Regulators of Mitochondrial Dynamics in Neurons.

Mitochondrial dynamics is a complex process, which involves the fission and fusion of mitochondrial outer and inner membranes. These processes organize the mitochondrial size and morphology, as well as their localization throughout the cells. In the last two decades, it has become a spotlight due to their importance in the pathophysiological processes, particularly in neurological diseases. It is known that Drp1, mitofusin 1 and 2, and Opa1 constitute the core of proteins that coordinate this intricate and dynamic process. Likewise, changes in the levels of reactive oxygen species (ROS) lead to modifications in the expression and/or activity of the proteins implicated in the mitochondrial dynamics, suggesting an involvement of these molecules in the process. In this review, we discuss the role of ROS in the regulation of fusion/fission in the nervous system, as well as the involvement of mitochondrial dynamics proteins in neurodegenerative diseases.

The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion.

Mitochondria are double-membrane-bound organelles that constantly change shape through membrane fusion and fission. Outer mitochondrial membrane fusion is controlled by Mitofusin, whose molecular architecture consists of an N-terminal GTPase domain, a first heptad repeat domain (HR1), two transmembrane domains, and a second heptad repeat domain (HR2). The mode of action of Mitofusin and the specific roles played by each of these functional domains in mitochondrial fusion are not fully understood. Here, using a combination of insitu and invitro fusion assays, we show that HR1 induces membrane fusion and possesses a conserved amphipathic helix that folds upon interaction with the lipid bilayer surface. Our results strongly suggest that HR1 facilitates membrane fusion by destabilizing the lipid bilayer structure, notably in membrane regions presenting lipid packing defects. This mechanism for fusion is thus distinct from that described for the heptad repeat domains of SNARE and viral proteins, which assemble as membrane-bridging complexes, triggering close membrane apposition and fusion, and is more closely related to that of the C-terminal amphipathic tail of the Atlastin protein.

Outer nuclear membrane fusion of adjacent nuclei in varicella-zoster virus-induced syncytia

Syncytia formation has been considered important for cell-to-cell spread and pathogenesis of many viruses. As a syncytium forms, individual nuclei often congregate together, allowing close contact of nuclear membranes and possibly fusion to occur. However, there is currently no reported evidence of nuclear membrane fusion between adjacent nuclei in wild-type virus-induced syncytia. Varicella-zoster virus (VZV) is one typical syncytia-inducing virus that causes chickenpox and shingles in humans. Here, we report, for the first time, an interesting observation of apparent fusion of the outer nuclear membranes from juxtaposed nuclei that comprise VZV syncytia both in ARPE-19 human epithelial cells in vitro and in human skin xenografts in the SCID-hu mouse model in vivo. This work reveals a novel aspect of VZV-related cytopathic effect in the context of multinucleated syncytia. Additionally, the information provided by this study could be helpful for future studies on interactions of viruses with host cell nuclei.