RT Journal Article
T1 Gemini-based lipoplexes complement the mitochondrial phenotype in MFN1-knockout mouse embryonic fibroblasts
A1 Muñoz Úbeda, Mónica
A1 Tolosa-Díaz, Andrés
A1 Bhattacharya, Santanu
A1 Junquera González, María Elena
A1 Aicart Sospedra, Emilio
A1 Natale, Paolo
A1 López Montero, Iván
AB 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.
PB ACS
SN 1543-8392
YR 2019
FD 2019
LK https://hdl.handle.net/20.500.14352/108889
UL https://hdl.handle.net/20.500.14352/108889
LA eng
NO Muñoz-Úbeda M, Tolosa-Díaz A, Bhattacharya S, Junquera E, Aicart E, Natale P, et al. Gemini-Based Lipoplexes Complement the Mitochondrial Phenotype in MFN1-Knockout Mouse Embryonic Fibroblasts. Mol Pharmaceutics 2019;16:4787–96. https://doi.org/10.1021/acs.molpharmaceut.9b00449
NO Consejo Europeo de Investigación (ERC)
NO Ministerio de Ciencia, Innovación y Universidades
DS Docta Complutense
RD 4 abr 2025