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

Munoz-Ubeda, Monica and Tolosa-Diaz, Andres and Bhattacharya, Santanu and Junquera, Elena and Aicart, Emilio and Natale, Paolo and Lopez-Montero, Ivan (2019) Gemini-Based Lipoplexes Complement the Mitochondrial Phenotype in MFN1-Knockout Mouse Embryonic Fibroblasts. In: MOLECULAR PHARMACEUTICS, 16 (12). pp. 4787-4796.

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Abstract

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 (Mfnl) and mitofusin 2 (Mfn2) are responsible for the fusion of the outer membrane of adjacent mitochondria. Mutations within Mfnl or Mfn2 impair mitochondrial fusion and lead to some severe mitochondrial dysfunctions and mitochondrial diseases (MDs). A characteristic phenotype of cells carrying defective Mfnl 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 Mfnl. A four-fold increase of the Mfnl 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:	Journal Article
Publication:	MOLECULAR PHARMACEUTICS
Publisher:	AMER CHEMICAL SOC
Additional Information:	Copyright of this article belongs to AMER CHEMICAL SOC
Keywords:	gemini cationic lipids (GCLs); mitofusin 1; lipoplexes; mitochondrial dynamics; mitochondrial diseases; gene therapy; drug delivery
Department/Centre:	Division of Chemical Sciences > Organic Chemistry
Date Deposited:	24 Dec 2019 09:26
Last Modified:	24 Dec 2019 09:26
URI:	http://eprints.iisc.ac.in/id/eprint/64197

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