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Gemini-Based Lipoplexes Complement the Mitochondrial Phenotype in MFN1-Knockout Mouse Embryonic Fibroblasts

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    Gemini-Based Lipoplexes Complement the Mitochondrial Phenotype in MFN1-Knockout Mouse Embryonic Fibroblasts
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    • Mónica Muñoz-Úbeda
      Mónica Muñoz-Úbeda
      Instituto de Investigación Hospital Doce de Octubre (i+12), Avenida de Córdoba s/n, 28041 Madrid, Spain
      More by Mónica Muñoz-Úbeda
    • Andrés Tolosa-Díaz
      Andrés Tolosa-Díaz
      Instituto de Investigación Hospital Doce de Octubre (i+12), Avenida de Córdoba s/n, 28041 Madrid, Spain
      Departamento de Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
      More by Andrés Tolosa-Díaz
    • Santanu Bhattacharya
      Santanu Bhattacharya
      Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
      More by Santanu Bhattacharya
      Orcidhttp://orcid.org/0000-0001-9040-8971
    • Elena Junquera
      Elena Junquera
      Departamento de Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
      More by Elena Junquera
      Orcidhttp://orcid.org/0000-0002-0655-5782
    • Emilio Aicart
      Emilio Aicart
      Departamento de Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
      More by Emilio Aicart
      Orcidhttp://orcid.org/0000-0003-1654-4136
    • Paolo Natale
      Paolo Natale
      Instituto de Investigación Hospital Doce de Octubre (i+12), Avenida de Córdoba s/n, 28041 Madrid, Spain
      Departamento de Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
      More by Paolo Natale
      Orcidhttp://orcid.org/0000-0002-4759-0816
    • Iván López-Montero*
      Iván López-Montero
      Instituto de Investigación Hospital Doce de Octubre (i+12), Avenida de Córdoba s/n, 28041 Madrid, Spain
      Departamento de Química Física, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040 Madrid, Spain
      *E-mail: [email protected]. Phone: +34 913945217.
      More by Iván López-Montero
      Orcidhttp://orcid.org/0000-0001-8131-6063
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2019, 16, 12, 4787–4796
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    https://doi.org/10.1021/acs.molpharmaceut.9b00449
    Published October 14, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Mitochondria form a dynamic network of constantly dividing and fusing organelles. The balance between these antagonistic processes is crucial for normal cellular function and requires the action of specialized proteins. The mitochondrial membrane proteins mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) are responsible for the fusion of the outer membrane of adjacent mitochondria. Mutations within Mfn1 or Mfn2 impair mitochondrial fusion and lead to some severe mitochondrial dysfunctions and mitochondrial diseases (MDs). A characteristic phenotype of cells carrying defective Mfn1 or Mfn2 is the presence of a highly fragmented mitochondrial network. Here, we use a biocompatible mixture of lipids, consisting on synthetic gemini cationic lipids (GCLs) and the zwitterionic phospholipid (DOPE), to complex, transport, and deliver intact copies of MFN1 gene into MFN1-Knockout mouse embryonic fibroblasts (MFN1-KO MEFs). We demonstrate that the GCL/DOPE-DNA lipoplexes are able to introduce the intact MFN1 gene into the cells and ectopically produce functional Mfn1. A four-fold increase of the Mfn1 levels is necessary to revert the MFN1-KO phenotype and to partially restore a mitochondrial network. This phenotype complementation was correlated with the transfection of GCL/DOPE-MFN1 lipoplexes that exhibited a high proportion of highly packaged hexagonal phase. GCL/DOPE-DNA lipoplexes are formulated as efficient therapeutic agents against MDs.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.9b00449.

    • Gating the determination of the effective charge of the GCL and the MYC-MFN1 plasmid and additional results needed to analyze the study reported in the MS (PDF)

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    This article is cited by 4 publications.

    1. Tan Zhang, Jingcheng Fan, Xin Wen, Xuemei Duan. ECSIT: Biological function and involvement in diseases. International Immunopharmacology 2024, 143 , 113524. https://doi.org/10.1016/j.intimp.2024.113524
    2. Meijuan Meng, Xuerui Li, Ran Huo, Nana Ma, Guangjun Chang, Xiangzhen Shen. A high-concentrate diet induces mitochondrial dysfunction by activating the MAPK signaling pathway in the mammary gland of dairy cows. Journal of Dairy Science 2023, 106 (8) , 5775-5787. https://doi.org/10.3168/jds.2022-22907
    3. Sergio González-Rubio, Cástor Salgado, Vanesa Manzaneda-González, Mónica Muñoz-Úbeda, Rubén Ahijado-Guzmán, Paolo Natale, Víctor G. Almendro-Vedia, Elena Junquera, José Osío Barcina, Irene Ferrer, Andrés Guerrero-Martínez, Luis Paz-Ares, Iván López-Montero. Tunable gold nanorod/NAO conjugates for selective drug delivery in mitochondria-targeted cancer therapy. Nanoscale 2022, 14 (22) , 8028-8040. https://doi.org/10.1039/D2NR02353A
    4. Mónica Muñoz-Úbeda, Martina Semenzato, Anais Franco-Romero, Elena Junquera, Emilio Aicart, Luca Scorrano, Iván López-Montero. Transgene expression in mice of the Opa1 mitochondrial transmembrane protein through bicontinuous cubic lipoplexes containing gemini imidazolium surfactants. Journal of Nanobiotechnology 2021, 19 (1) https://doi.org/10.1186/s12951-021-01167-x
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2019, 16, 12, 4787–4796
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.9b00449
    Published October 14, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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