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



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Muñoz Úbeda, Mónica and Tolosa Díaz, Andrés and Bhattacharya, Santanu and Junquera González, Elena and Aicart Sospedra, Emilio and Natale, Paolo and López-Montero, Iván (2019) Gemini-Based Lipoplexes Complement the Mitochondrial Phenotype in MFN1-Knockout Mouse Embryonic Fibroblasts. Molecular Pharmaceutics, 16 (12). ISSN 1543-8384

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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.

Item Type:Article
Uncontrolled Keywords:Gemini cationic lipids (GCLs), mitofusin 1, lipoplexes, mitochondrial dynamics, mitochondrial diseases, gene therapy, drug delivery
Subjects:Medical sciences > Biology > Biotechnology
Medical sciences > Pharmacy > Physical chemistry
ID Code:60123
Deposited On:23 Apr 2020 07:47
Last Modified:23 Apr 2020 07:47

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