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Articoli di riviste sul tema "Mitofusins"

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Autore: Grafiati

Pubblicato: 22 giugno 2024

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1

Cohen, Mickael M., e David Tareste. "Recent insights into the structure and function of Mitofusins in mitochondrial fusion". F1000Research 7 (28 dicembre 2018): 1983. http://dx.doi.org/10.12688/f1000research.16629.1.

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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.

2

Wolf, Christina, Víctor López del Amo, Sabine Arndt, Diones Bueno, Stefan Tenzer, Eva-Maria Hanschmann, Carsten Berndt e Axel Methner. "Redox Modifications of Proteins of the Mitochondrial Fusion and Fission Machinery". Cells 9, n. 4 (27 marzo 2020): 815. http://dx.doi.org/10.3390/cells9040815.

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Mitochondrial fusion and fission tailors the mitochondrial shape to changes in cellular homeostasis. Players of this process are the mitofusins, which regulate fusion of the outer mitochondrial membrane, and the fission protein DRP1. Upon specific stimuli, DRP1 translocates to the mitochondria, where it interacts with its receptors FIS1, MFF, and MID49/51. Another fission factor of clinical relevance is GDAP1. Here, we identify and discuss cysteine residues of these proteins that are conserved in phylogenetically distant organisms and which represent potential sites of posttranslational redox modifications. We reveal that worms and flies possess only a single mitofusin, which in vertebrates diverged into MFN1 and MFN2. All mitofusins contain four conserved cysteines in addition to cysteine 684 in MFN2, a site involved in mitochondrial hyperfusion. DRP1 and FIS1 are also evolutionarily conserved but only DRP1 contains four conserved cysteine residues besides cysteine 644, a specific site of nitrosylation. MFF and MID49/51 are only present in the vertebrate lineage. GDAP1 is missing in the nematode genome and contains no conserved cysteine residues. Our analysis suggests that the function of the evolutionarily oldest proteins of the mitochondrial fusion and fission machinery, the mitofusins and DRP1 but not FIS1, might be altered by redox modifications.

3

LeBrasseur, Nicole. "Pro-diversity mitofusins". Journal of Cell Biology 176, n. 4 (12 febbraio 2007): 373a. http://dx.doi.org/10.1083/jcb.1764iti3.

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4

Schiavon, Cara R., Rachel E. Turn, Laura E. Newman e Richard A. Kahn. "ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2". Molecular Biology of the Cell 30, n. 10 (maggio 2019): 1198–213. http://dx.doi.org/10.1091/mbc.e18-12-0804.

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Mitochondria are essential and dynamic organelles undergoing constant fission and fusion. The primary players in mitochondrial morphology (MFN1/2, OPA1, DRP1) have been identified, but their mechanism(s) of regulation are still being elucidated. ARL2 is a regulatory GTPase that has previously been shown to play a role in the regulation of mitochondrial morphology. Here we demonstrate that ELMOD2, an ARL2 GTPase-activating protein (GAP), is necessary for ARL2 to promote mitochondrial elongation. We show that loss of ELMOD2 causes mitochondrial fragmentation and a lower rate of mitochondrial fusion, while ELMOD2 overexpression promotes mitochondrial tubulation and increases the rate of fusion in a mitofusin-dependent manner. We also show that a mutant of ELMOD2 lacking GAP activity is capable of promoting fusion, suggesting that ELMOD2 does not need GAP activity to influence mitochondrial morphology. Finally, we show that ELMOD2, ARL2, Mitofusins 1 and 2, Miros 1 and 2, and mitochondrial phospholipase D (mitoPLD) all localize to discrete, regularly spaced puncta along mitochondria. These results suggest that ELMOD2 is functioning as an effector downstream of ARL2 and upstream of the mitofusins to promote mitochondrial fusion. Our data provide insights into the pathway by which mitochondrial fusion is regulated in the cell.

5

Koch, Linda. "Mitofusins and energy balance". Nature Reviews Endocrinology 9, n. 12 (15 ottobre 2013): 691. http://dx.doi.org/10.1038/nrendo.2013.202.

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6

Escobar-Henriques, Mafalda. "Mitofusins: ubiquitylation promotes fusion". Cell Research 24, n. 4 (21 febbraio 2014): 387–88. http://dx.doi.org/10.1038/cr.2014.23.

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7

Miao, Junru, Wei Chen, Pengxiang Wang, Xin Zhang, Lei Wang, Shuai Wang e Yuan Wang. "MFN1 and MFN2 Are Dispensable for Sperm Development and Functions in Mice". International Journal of Molecular Sciences 22, n. 24 (16 dicembre 2021): 13507. http://dx.doi.org/10.3390/ijms222413507.

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MFN1 (Mitofusin 1) and MFN2 (Mitofusin 2) are GTPases essential for mitochondrial fusion. Published studies revealed crucial roles of both Mitofusins during embryonic development. Despite the unique mitochondrial organization in sperm flagella, the biological requirement in sperm development and functions remain undefined. Here, using sperm-specific Cre drivers, we show that either Mfn1 or Mfn2 knockout in haploid germ cells does not affect male fertility. The Mfn1 and Mfn2 double knockout mice were further analyzed. We found no differences in testis morphology and weight between Mfn-deficient mice and their wild-type littermate controls. Spermatogenesis was normal in Mfn double knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules, indicating that sperm formation was not disrupted upon MFN deficiency. Collectively, our findings reveal that both MFN1 and MFN2 are dispensable for sperm development and functions in mice.

8

Sloat, S. R., B. N. Whitley, E. A. Engelhart e S. Hoppins. "Identification of a mitofusin specificity region that confers unique activities to Mfn1 and Mfn2". Molecular Biology of the Cell 30, n. 17 (agosto 2019): 2309–19. http://dx.doi.org/10.1091/mbc.e19-05-0291.

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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.

9

Alsayyah, Cynthia, Manish K. Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner et al. "Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion". PLOS Biology 22, n. 4 (26 aprile 2024): e3002602. http://dx.doi.org/10.1371/journal.pbio.3002602.

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Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these “PerMit” contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin–proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.

10

R. Khalil, Rana, Mufeda AL-Ammar e Hayder A. L. Mossa. "Mitofusin 1 as Marker of Oocyte Maturation in Relevance to ICSI Outcome in Infertile Females". IraQi Journal of Embryos and Infertility Researches 13, n. 2 (8 novembre 2023): 39–50. http://dx.doi.org/10.28969/ijeir.v13.i2.r4.23.

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Pro-fusion proteins as mitofusins-1 are required for controlling mitochondrial shape which determined by a dynamic balance between organelle fusion and fission and also supports oocyte development. When compare with somatic cell, mitochondria of oocyte are tiny and circular in presence. The aim is to study the mitofusin-1 in the follicular fluid as a marker for evaluating of oocyte maturation in women undergoing ICSI cycles. Fifty infertile females were included in cross-section study was undergoing ICSI procedure with age 20 to 42 years. After retrieval of oocyte and the number of oocytes was recorded by embryologist and follicular fluid Samples were used for the measurement of Mitofusin 1. Mitofusin 1 levels by ELISA kit (Mybiosource /USA).The results showed considerable higher mitofusin1levels in patients with good oocytes quality (3.71 ± 1.35 vs. 2.45 ± 1.12 & p=0.001). There were much positive correlations between follicular fluids mitofusin-1 with both total oocytes count (r= 0.374 & p= 0.007) and MII oocytes (r=0.383 & p=0.006); and there was no much correlation between mitofusin-1 levels with MI oocyte (r= - 0.100 & p= 0.490), germinal vesical oocyte (r=0.103 & p= 0.475) and fertilization rate (r= 0.054 & p= 0.711). High follicular fluid levels of Mitofusin 1 may positively impact oocyte development and pregnancy rate.

11

Schrepfer, Emilie, e Luca Scorrano. "Mitofusins, from Mitochondria to Metabolism". Molecular Cell 61, n. 5 (marzo 2016): 683–94. http://dx.doi.org/10.1016/j.molcel.2016.02.022.

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12

Ozcan, Umut. "Mitofusins: Mighty Regulators of Metabolism". Cell 155, n. 1 (settembre 2013): 17–18. http://dx.doi.org/10.1016/j.cell.2013.09.013.

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13

Brooks, Craig, Sung-Gyu Cho, Cong-Yi Wang, Tianxin Yang e Zheng Dong. "Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis". American Journal of Physiology-Cell Physiology 300, n. 3 (marzo 2011): C447—C455. http://dx.doi.org/10.1152/ajpcell.00402.2010.

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Recent studies have shown mitochondrial fragmentation during cell stress and have suggested a role for the morphological change in mitochondrial injury and ensuing apoptosis. However, the underlying mechanism remains elusive. Here we demonstrate that mitochondrial fragmentation facilitates Bax insertion and activation in mitochondria, resulting in the release of apoptogenic factors. In HeLa cells, overexpression of mitofusins attenuated mitochondrial fragmentation during cisplatin- and azide-induced cell injury, which was accompanied by less apoptosis and less cytochrome c release from mitochondria. Similar effects were shown by inhibiting the mitochondrial fission protein Drp1 with a dominant negative mutant (dn-Drp1). Mitofusins and dn-Drp1 did not seem to significantly affect Bax translocation/accumulation to mitochondria; however, they blocked Bax insertion and activation in mitochondrial membrane. Consistently, in rat kidney proximal tubular cells, small interfering RNA knockdown of Drp1 prevented mitochondrial fragmentation during azide-induced ATP depletion, which was accompanied by less Bax activation, insertion, and oligomerization in mitochondria. These cells released less cytochrome c and AIF from mitochondria and showed significantly lower apoptosis. Finally, mitofusin-null mouse embryonic fibroblasts (MEF) had fragmented mitochondria. These MEFs were more sensitive to cisplatin-induced Bax activation, release of cytochrome c, and apoptosis. Together, this study provides further support for a role of mitochondrial fragmentation in mitochondrial injury and apoptosis. Mechanistically, mitochondrial fragmentation may sensitize the cells to Bax insertion and activation in mitochondria, facilitating the release of apoptogenic factors and consequent apoptosis.

14

Giacomello, Marta, e Luca Scorrano. "The INs and OUTs of mitofusins". Journal of Cell Biology 217, n. 2 (18 gennaio 2018): 439–40. http://dx.doi.org/10.1083/jcb.201801042.

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Mitofusins are outer membrane proteins essential for mitochondrial fusion. Their accepted topology posits that both N and C termini face the cytoplasm. In this issue, Mattie et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201611194) demonstrate instead that their C termini reside in the intermembrane space. These findings call for a revision of the current models of mitochondrial fusion.

15

Dorn, Gerald W. "Mitofusins as mitochondrial anchors and tethers". Journal of Molecular and Cellular Cardiology 142 (maggio 2020): 146–53. http://dx.doi.org/10.1016/j.yjmcc.2020.04.016.

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16

Parekh, Anant. "Calcium Signalling: Mitofusins Promote Interorganellar Crosstalk". Current Biology 19, n. 5 (marzo 2009): R200—R203. http://dx.doi.org/10.1016/j.cub.2009.01.012.

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17

Engelhart, Emily A., e Suzanne Hoppins. "A catalytic domain variant of mitofusin requiring a wildtype paralog for function uncouples mitochondrial outer-membrane tethering and fusion". Journal of Biological Chemistry 294, n. 20 (1 aprile 2019): 8001–14. http://dx.doi.org/10.1074/jbc.ra118.006347.

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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.

18

Anton, Vincent, Ira Buntenbroich, Ramona Schuster, Felix Babatz, Tânia Simões, Selver Altin, Gaetano Calabrese, Jan Riemer, Astrid Schauss e Mafalda Escobar-Henriques. "Plasticity in salt bridge allows fusion-competent ubiquitylation of mitofusins and Cdc48 recognition". Life Science Alliance 2, n. 6 (18 novembre 2019): e201900491. http://dx.doi.org/10.26508/lsa.201900491.

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Mitofusins are dynamin-related GTPases that drive mitochondrial fusion by sequential events of oligomerization and GTP hydrolysis, followed by their ubiquitylation. Here, we show that fusion requires a trilateral salt bridge at a hinge point of the yeast mitofusin Fzo1, alternatingly forming before and after GTP hydrolysis. Mutations causative of Charcot–Marie–Tooth disease massively map to this hinge point site, underlining the disease relevance of the trilateral salt bridge. A triple charge swap rescues the activity of Fzo1, emphasizing the close coordination of the hinge residues with GTP hydrolysis. Subsequently, ubiquitylation of Fzo1 allows the AAA-ATPase ubiquitin-chaperone Cdc48 to resolve Fzo1 clusters, releasing the dynamin for the next fusion round. Furthermore, cross-complementation within the oligomer unexpectedly revealed ubiquitylated but fusion-incompetent Fzo1 intermediates. However, Cdc48 did not affect the ubiquitylated but fusion-incompetent variants, indicating that Fzo1 ubiquitylation is only controlled after membrane merging. Together, we present an integrated model on how mitochondrial outer membranes fuse, a critical process for their respiratory function but also putatively relevant for therapeutic interventions.

19

Song, Zhiyin, Mariam Ghochani, J. Michael McCaffery, Terrence G. Frey e David C. Chan. "Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion". Molecular Biology of the Cell 20, n. 15 (agosto 2009): 3525–32. http://dx.doi.org/10.1091/mbc.e09-03-0252.

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Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases—OPA1 and the mitofusins Mfn1 and Mfn2—are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast.

20

Mattie, Sevan, Jan Riemer, Jeremy G. Wideman e Heidi M. McBride. "A new mitofusin topology places the redox-regulated C terminus in the mitochondrial intermembrane space". Journal of Cell Biology 217, n. 2 (6 dicembre 2017): 507–15. http://dx.doi.org/10.1083/jcb.201611194.

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Mitochondrial fusion occurs in many eukaryotes, including animals, plants, and fungi. It is essential for cellular homeostasis, and yet the underlying mechanisms remain elusive. Comparative analyses and phylogenetic reconstructions revealed that fungal Fzo1 and animal Mitofusin proteins are highly diverged from one another and lack strong sequence similarity. Bioinformatic analysis showed that fungal Fzo1 proteins exhibit two predicted transmembrane domains, whereas metazoan Mitofusins contain only a single transmembrane domain. This prediction contradicts the current models, suggesting that both animal and fungal proteins share one topology. This newly predicted topology of Mfn1 and Mfn2 was demonstrated biochemically, confirming that the C-terminal, redox-sensitive cysteine residues reside within the intermembrane space (IMS). Functional experiments established that redox-mediated disulfide modifications within the IMS domain are key modulators of reversible Mfn oligomerization that drives fusion. Together, these results lead to a revised understanding of Mfns as single-spanning outer membrane proteins with an Nout–Cin orientation, providing functional insight into the IMS contribution to redox-regulated fusion events.

21

De Vecchis, Dario, Antoine Taly, Marc Baaden e Jérôme Hénin. "Mitochondrial Membrane Fusion: Computational Modeling of Mitofusins". Biophysical Journal 110, n. 3 (febbraio 2016): 571a. http://dx.doi.org/10.1016/j.bpj.2015.11.3054.

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22

Papanicolaou, Kyriakos N., Matthew M. Phillippo e Kenneth Walsh. "Mitofusins and the mitochondrial permeability transition: the potential downside of mitochondrial fusion". American Journal of Physiology-Heart and Circulatory Physiology 303, n. 3 (1 agosto 2012): H243—H255. http://dx.doi.org/10.1152/ajpheart.00185.2012.

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Mitofusins (Mfn-1 and Mfn-2) are transmembrane proteins that bind and hydrolyze guanosine 5′-triphosphate to bring about the merging of adjacent mitochondrial membranes. This event is necessary for mitochondrial fusion, a biological process that is critical for organelle function. The broad effects of mitochondrial fusion on cell bioenergetics have been extensively studied, whereas the local effects of mitofusin activity on the structure and integrity of the fusing mitochondrial membranes have received relatively little attention. From the study of fusogenic proteins, theoretical models, and simulations, it has been noted that the fusion of biological membranes is associated with local perturbations on the integrity of the membrane that present in the form of lipidic holes which open on the opposing bilayers. These lipidic holes represent obligate intermediates that make the fusion process thermodynamically more favorable and at the same time induce leakage to the fusing membranes. In this perspectives article we present the relevant evidence selected from a spectrum of membrane fusion/leakage models and attempt to couple this information with observations conducted with cardiac myocytes or mitochondria deficient in Mfn-1 and Mfn-2. More specifically, we argue in favor of a situation whereby mitochondrial fusion in cardiac myocytes is coupled with outer mitochondrial membrane destabilization that is opportunistically employed during the process of mitochondrial permeability transition. We hope that these insights will initiate research on this new hypothesis of mitochondrial permeability transition regulation, a poorly understood mitochondrial function with significant consequences on myocyte survival.

23

Schuster, Ramona, Vincent Anton, Tânia Simões, Selver Altin, Fabian den Brave, Thomas Hermanns, Manuela Hospenthal et al. "Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation". Life Science Alliance 3, n. 1 (19 dicembre 2019): e201900476. http://dx.doi.org/10.26508/lsa.201900476.

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Mitochondria are essential organelles whose function is upheld by their dynamic nature. This plasticity is mediated by large dynamin-related GTPases, called mitofusins in the case of fusion between two mitochondrial outer membranes. Fusion requires ubiquitylation, attached to K398 in the yeast mitofusin Fzo1, occurring in atypical and conserved forms. Here, modelling located ubiquitylation to α4 of the GTPase domain, a critical helix in Ras-mediated events. Structure-driven analysis revealed a dual role of K398. First, it is required for GTP-dependent dynamic changes of α4. Indeed, mutations designed to restore the conformational switch, in the absence of K398, rescued wild-type-like ubiquitylation on Fzo1 and allowed fusion. Second, K398 is needed for Fzo1 recognition by the pro-fusion factors Cdc48 and Ubp2. Finally, the atypical ubiquitylation pattern is stringently required bilaterally on both involved mitochondria. In contrast, exchange of the conserved pattern with conventional ubiquitin chains was not sufficient for fusion. In sum, α4 lysines from both small and large GTPases could generally have an electrostatic function for membrane interaction, followed by posttranslational modifications, thus driving membrane fusion events.

24

Son, M. J., Y. Kwon, M.-Y. Son, B. Seol, H.-S. Choi, S.-W. Ryu, C. Choi e Y. S. Cho. "Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency". Cell Death & Differentiation 22, n. 12 (17 aprile 2015): 1957–69. http://dx.doi.org/10.1038/cdd.2015.43.

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25

Yu, Chia-Yi, Jian-Jong Liang, Jin-Kun Li, Yi-Ling Lee, Bi-Lan Chang, Chan-I. Su, Wei-Jheng Huang, Michael M. C. Lai e Yi-Ling Lin. "Dengue Virus Impairs Mitochondrial Fusion by Cleaving Mitofusins". PLOS Pathogens 11, n. 12 (30 dicembre 2015): e1005350. http://dx.doi.org/10.1371/journal.ppat.1005350.

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26

Mourier, Arnaud, Elisa Motori, Eduardo Silva Ramos, Tobias Brandt, Marie Lagouge, Ilian Atanassov, Anne Galinier et al. "Role of Mitofusins proteins in maintaining OXPHOS function". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1857 (agosto 2016): e15. http://dx.doi.org/10.1016/j.bbabio.2016.04.386.

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27

Santel, A., e M. T. Fuller. "Control of mitochondrial morphology by a human mitofusin". Journal of Cell Science 114, n. 5 (1 marzo 2001): 867–74. http://dx.doi.org/10.1242/jcs.114.5.867.

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Abstract (sommario):

Although changes in mitochondrial size and arrangement accompany both cellular differentiation and human disease, the mechanisms that mediate mitochondrial fusion, fission and morphogenesis in mammalian cells are not understood. We have identified two human genes encoding potential mediators of mitochondrial fusion. The mitofusins (Mfn1 and Mfn2) are homologs of the Drosophila protein fuzzy onion (Fzo) that associate with mitochondria and alter mitochondrial morphology when expressed by transient transfection in tissue culture cells. An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria and requires hydrophobic residues within the TM. Co-expression of Mfn2 with a dominant interfering mutant dynamin-related protein (Drp1(K38A)) proposed to block mitochondrial fission resulted in long mitochondrial filaments and networks. Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion and that mitofusins and dynamin related GTPases play opposing roles in mitochondrial fusion and fission in mammals, as in yeast.

28

Tanaka, Atsushi, Megan M. Cleland, Shan Xu, Derek P. Narendra, Der-Fen Suen, Mariusz Karbowski e Richard J. Youle. "Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin". Journal of Cell Biology 191, n. 7 (20 dicembre 2010): 1367–80. http://dx.doi.org/10.1083/jcb.201007013.

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Damage to mitochondria can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. However, fusion of uncoupled mitochondria with polarized mitochondria can compensate for damage, reverse membrane depolarization, and obviate mitophagy. Parkin, an E3 ubiquitin ligase that is mutated in monogenic forms of Parkinson’s disease, was recently found to induce selective autophagy of damaged mitochondria. Here we show that ubiquitination of mitofusins Mfn1 and Mfn2, large GTPases that mediate mitochondrial fusion, is induced by Parkin upon membrane depolarization and leads to their degradation in a proteasome- and p97-dependent manner. p97, a AAA+ ATPase, accumulates on mitochondria upon uncoupling of Parkin-expressing cells, and both p97 and proteasome activity are required for Parkin-mediated mitophagy. After mitochondrial fission upon depolarization, Parkin prevents or delays refusion of mitochondria, likely by the elimination of mitofusins. Inhibition of Drp1-mediated mitochondrial fission, the proteasome, or p97 prevents Parkin-induced mitophagy.

29

Samanas, Nyssa B., Emily A. Engelhart e Suzanne Hoppins. "Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax". Life Science Alliance 3, n. 5 (3 aprile 2020): e201900527. http://dx.doi.org/10.26508/lsa.201900527.

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Mitofusins are members of the dynamin-related protein family of large GTPases that harness the energy from nucleotide hydrolysis to remodel membranes. Mitofusins possess four structural domains, including a GTPase domain, two extended helical bundles (HB1 and HB2), and a transmembrane region. We have characterized four Charcot-Marie-Tooth type 2A–associated variants with amino acid substitutions in Mfn2 that are proximal to the hinge that connects HB1 and HB2. A functional defect was not apparent in cells as the mitochondrial morphology of Mfn2-null cells was restored by expression of any of these variants. However, a significant fusion deficiency was observed in vitro, which was improved by the addition of crude cytosol extract or soluble Bax. All four variants had reduced nucleotide-dependent assembly in cis, but not trans, and this was also improved by the addition of Bax. Together, our data demonstrate an important role for this region in Mfn2 GTP-dependent oligomerization and membrane fusion and is consistent with a model where cytosolic factors such as Bax are masking molecular defects associated with Mfn2 disease variants in cells.

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Pellattiero, Anna, e Luca Scorrano. "Flaming Mitochondria: The Anti-inflammatory Drug Leflunomide Boosts Mitofusins". Cell Chemical Biology 25, n. 3 (marzo 2018): 231–33. http://dx.doi.org/10.1016/j.chembiol.2018.02.014.

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31

Zhang, Lihong, Xiawei Dang, Antonietta Franco, Haiyang Zhao e Gerald W. Dorn. "Piperine Derivatives Enhance Fusion and Axonal Transport of Mitochondria by Activating Mitofusins". Chemistry 4, n. 3 (23 giugno 2022): 655–68. http://dx.doi.org/10.3390/chemistry4030047.

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Abstract (sommario):

Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum of pharmacological activities. The molecular bases for many of piperine’s biological effects are incompletely defined. We noted that the chemical structure of piperine generally conforms to a pharmacophore model for small bioactive molecules that activate mitofusin (MFN)-mediated mitochondrial fusion. Piperine, but not its isomer chavicine, stimulated mitochondrial fusion in MFN-deficient cells with EC50 of ~8 nM. We synthesized piperine analogs having structural features predicted to optimize mitofusin activation and defined structure-activity relationships (SAR) in live-cell mitochondrial elongation assays. When optimal spacing was maintained between amide and aromatic groups the derivatives were potent mitofusin activators. Compared to the prototype phenylhexanamide mitofusin activator, 2, novel molecules containing the piperidine structure of piperine exhibited markedly enhanced passive membrane permeability with no loss of fusogenic potency. Lead compounds 5 and 8 enhanced mitochondrial motility in cultured murine Charcot-Marie-Tooth disease type 2A (CMT2A) neurons, but only 8 improved mitochondrial transport in sciatic nerve axons of CMT2A mice. Piperine analogs represent a new chemical class of mitofusin activators with potential pharmaceutical advantages.

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Ryan, Michael T., e Diana Stojanovski. "Mitofusins ‘bridge’ the gap between oxidative stress and mitochondrial hyperfusion". EMBO reports 13, n. 10 (11 settembre 2012): 870–71. http://dx.doi.org/10.1038/embor.2012.132.

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Daumke, Oliver, e Aurélien Roux. "Mitochondrial Homeostasis: How Do Dimers of Mitofusins Mediate Mitochondrial Fusion?" Current Biology 27, n. 9 (maggio 2017): R353—R356. http://dx.doi.org/10.1016/j.cub.2017.03.024.

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Santel, Ansgar. "Get the balance right: Mitofusins roles in health and disease". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1763, n. 5-6 (maggio 2006): 490–99. http://dx.doi.org/10.1016/j.bbamcr.2006.02.004.

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Ding, Wen-Xing, Fengli Guo, Hong-Min Ni, Abigail Bockus, Sharon Manley, Donna B. Stolz, Eeva-Liisa Eskelinen, Hartmut Jaeschke e Xiao-Ming Yin. "Parkin and Mitofusins Reciprocally Regulate Mitophagy and Mitochondrial Spheroid Formation". Journal of Biological Chemistry 287, n. 50 (24 ottobre 2012): 42379–88. http://dx.doi.org/10.1074/jbc.m112.413682.

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Vlieghe, Anaïs, Kristina Niort, Hugo Fumat, Jean-Michel Guigner, Mickaël M. Cohen e David Tareste. "Role of Lipids and Divalent Cations in Membrane Fusion Mediated by the Heptad Repeat Domain 1 of Mitofusin". Biomolecules 13, n. 9 (2 settembre 2023): 1341. http://dx.doi.org/10.3390/biom13091341.

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Abstract (sommario):

Mitochondria are highly dynamic organelles that constantly undergo fusion and fission events to maintain their shape, distribution and cellular function. Mitofusin 1 and 2 proteins are two dynamin-like GTPases involved in the fusion of outer mitochondrial membranes (OMM). Mitofusins are anchored to the OMM through their transmembrane domain and possess two heptad repeat domains (HR1 and HR2) in addition to their N-terminal GTPase domain. The HR1 domain was found to induce fusion via its amphipathic helix, which interacts with the lipid bilayer structure. The lipid composition of mitochondrial membranes can also impact fusion. However, the precise mode of action of lipids in mitochondrial fusion is not fully understood. In this study, we examined the role of the mitochondrial lipids phosphatidylethanolamine (PE), cardiolipin (CL) and phosphatidic acid (PA) in membrane fusion induced by the HR1 domain, both in the presence and absence of divalent cations (Ca2+ or Mg2+). Our results showed that PE, as well as PA in the presence of Ca2+, effectively stimulated HR1-mediated fusion, while CL had a slight inhibitory effect. By considering the biophysical properties of these lipids in the absence or presence of divalent cations, we inferred that the interplay between divalent cations and specific cone-shaped lipids creates regions with packing defects in the membrane, which provides a favorable environment for the amphipathic helix of HR1 to bind to the membrane and initiate fusion.

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Ugarte-Uribe, Begoña, e Ana J. García-Sáez. "Membranes in motion: mitochondrial dynamics and their role in apoptosis". Biological Chemistry 395, n. 3 (1 marzo 2014): 297–311. http://dx.doi.org/10.1515/hsz-2013-0234.

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Abstract Mitochondrial dynamics is crucial for cell survival, development and homeostasis and impairment of these functions leads to neurologic disorders and metabolic diseases. The key components of mitochondrial dynamics have been identified. Mitofusins and OPA1 mediate mitochondrial fusion, whereas Drp1 is responsible for mitochondrial fission. In addition, an interplay between the proteins of the mitochondrial fission/fusion machinery and the Bcl-2 proteins, essential mediators in apoptosis, has been also described. Here, we review the molecular mechanisms regarding mitochondrial dynamics together with their role in apoptosis.

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Papanicolaou, Kyriakos N., Ryosuke Kikuchi, Gladys A. Ngoh, Kimberly A. Coughlan, Isabel Dominguez, William C. Stanley e Kenneth Walsh. "Mitofusins 1 and 2 Are Essential for Postnatal Metabolic Remodeling in Heart". Circulation Research 111, n. 8 (28 settembre 2012): 1012–26. http://dx.doi.org/10.1161/circresaha.112.274142.

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Rakovic, Aleksandar, Anne Grünewald, Jan Kottwitz, Norbert Brüggemann, Peter P. Pramstaller, Katja Lohmann e Christine Klein. "Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts". PLoS ONE 6, n. 3 (8 marzo 2011): e16746. http://dx.doi.org/10.1371/journal.pone.0016746.

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Brooks, C., Q. Wei, L. Feng, G. Dong, Y. Tao, L. Mei, Z. J. Xie e Z. Dong. "Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins". Proceedings of the National Academy of Sciences 104, n. 28 (2 luglio 2007): 11649–54. http://dx.doi.org/10.1073/pnas.0703976104.

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41

Du, Mengyan, Si Yu, Wenhua Su, Mengxin Zhao, Fangfang Yang, Yangpei Liu, Zihao Mai, Yong Wang, Xiaoping Wang e Tongsheng Chen. "Mitofusin 2 but not mitofusin 1 mediates Bcl-XL-induced mitochondrial aggregation". Journal of Cell Science 133, n. 20 (21 settembre 2020): jcs245001. http://dx.doi.org/10.1242/jcs.245001.

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Abstract (sommario):

ABSTRACTBcl-2 family proteins, as central players of the apoptotic program, participate in regulation of the mitochondrial network. Here, a quantitative live-cell fluorescence resonance energy transfer (FRET) two-hybrid assay was used to confirm the homo-/hetero-oligomerization of mitofusins 2 and 1 (MFN2 and MFN1), and also demonstrate the binding of MFN2 to MFN1 with 1:1 stoichiometry. A FRET two-hybrid assay for living cells co-expressing CFP-labeled Bcl-XL (an anti-apoptotic Bcl-2 family protein encoded by BCL2L1) and YFP-labeled MFN2 or MFN1 demonstrated the binding of MFN2 or MFN1 to Bcl-XL with 1:1 stoichiometry. Neither MFN2 nor MFN1 bound with monomeric Bax in healthy cells, but both MFN2 and MFN1 bind to punctate Bax (pro-apoptotic Bcl-2 family protein) during apoptosis. Oligomerized Bak (also known as BAK1; a pro-apoptotic Bcl-2 family protein) only associated with MFN1 but not MFN2. Moreover, co-expression of Bcl-XL with MFN2 or MFN1 had the same anti-apoptotic effect as the expression of Bcl-XL alone to staurosporine-induced apoptosis, indicating the Bcl-XL has its full anti-apoptotic ability when complexed with MFN2 or MFN1. However, knockdown of MFN2 but not MFN1 reduced mitochondrial aggregation induced by overexpression of Bcl-XL, indicating that MFN2 but not MFN1 mediates Bcl-XL-induced mitochondrial aggregation.

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Wiedemann, Nils, Sebastian B. Stiller e Nikolaus Pfanner. "Activation and Degradation of Mitofusins: Two Pathways Regulate Mitochondrial Fusion by Reversible Ubiquitylation". Molecular Cell 49, n. 3 (febbraio 2013): 423–25. http://dx.doi.org/10.1016/j.molcel.2013.01.027.

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43

Yin, Xiao-Ming, e Wen-Xing Ding. "The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation". Autophagy 9, n. 11 (3 novembre 2013): 1687–92. http://dx.doi.org/10.4161/auto.24871.

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Dietrich, Marcelo O., Zhong-Wu Liu e Tamas L. Horvath. "Mitochondrial Dynamics Controlled by Mitofusins Regulate Agrp Neuronal Activity and Diet-Induced Obesity". Cell 155, n. 1 (settembre 2013): 188–99. http://dx.doi.org/10.1016/j.cell.2013.09.004.

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45

Lee, Crystal A., Lih-Shen Chin e Lian Li. "Hypertonia-linked protein Trak1 functions with mitofusins to promote mitochondrial tethering and fusion". Protein & Cell 9, n. 8 (18 settembre 2017): 693–716. http://dx.doi.org/10.1007/s13238-017-0469-4.

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Bhatia, Divya, Eleni Kallinos, Edwin Patino, Maria Plataki, Augustine M. Choi e Mary E. Choi. "Alveolar Type II Cell-Specific Mitofusins Modulate Kidney Fibrosis and Associated Lung Injury". Journal of the American Society of Nephrology 34, n. 11S (novembre 2023): 701. http://dx.doi.org/10.1681/asn.20233411s1701b.

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Wakai, Takuya, Yuichirou Harada, Kenji Miyado e Tomohiro Kono. "Mitochondrial dynamics controlled by mitofusins define organelle positioning and movement during mouse oocyte maturation". MHR: Basic science of reproductive medicine 20, n. 11 (11 agosto 2014): 1090–100. http://dx.doi.org/10.1093/molehr/gau064.

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Chen, Hsiuchen, Scott A. Detmer, Andrew J. Ewald, Erik E. Griffin, Scott E. Fraser e David C. Chan. "Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development". Journal of Cell Biology 160, n. 2 (13 gennaio 2003): 189–200. http://dx.doi.org/10.1083/jcb.200211046.

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Abstract (sommario):

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.

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Wu, Zhaofei, Yushan Zhu, Xingshui Cao, Shufeng Sun e Baolu Zhao. "Mitochondrial Toxic Effects of Aβ Through Mitofusins in the Early Pathogenesis of Alzheimer’s Disease". Molecular Neurobiology 50, n. 3 (8 aprile 2014): 986–96. http://dx.doi.org/10.1007/s12035-014-8675-z.

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Nakamura, Nobuhiro, e Shigehisa Hirose. "Regulation of Mitochondrial Morphology by USP30, a Deubiquitinating Enzyme Present in the Mitochondrial Outer Membrane". Molecular Biology of the Cell 19, n. 5 (maggio 2008): 1903–11. http://dx.doi.org/10.1091/mbc.e07-11-1103.

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Abstract (sommario):

Recent studies have suggested that ubiquitination of mitochondrial proteins participates in regulating mitochondrial dynamics in mammalian cells, but it is unclear whether deubiquitination is involved in this process. Here, we identify human ubiquitin-specific protease 30 (USP30) as a deubiquitinating enzyme that is embedded in the mitochondrial outer membrane. Depletion of USP30 expression by RNA interference induced elongated and interconnected mitochondria, depending on the activities of the mitochondrial fusion factors mitofusins, without changing the expression levels of the key regulators for mitochondrial dynamics. Mitochondria were rescued from this abnormal phenotype by ectopic expression of USP30 in a manner dependent on its enzymatic activity. Our findings reveal that USP30 participates in the maintenance of mitochondrial morphology, a finding that provides new insight into the cellular function of deubiquitination.