3 years ago

Import of TAT-conjugated propionyl-CoA carboxylase using models of propionic acidemia.

Renata Collard, Insun Park, Jan P Kraus, Tomas Majtan
Propionic acidemia is caused by a deficiency of the enzyme propionyl-CoA carboxylase (PCC) located in the mitochondrial matrix. Cell-penetrating peptides, including TAT, offer a potential to deliver a cargo into the mitochondrion. Here, we investigated the delivery of an α6β6 PCC enzyme into mitochondria using HIV transactivator of transcription (TAT) peptide at several levels: into isolated mitochondria, patient fibroblast cells and a mouse model. Western blotting of mitochondria as well as enzyme activity confirmed the import of a fusion TAT-PCC into mitochondria as well as into patient cells and the mitochondrial localization was confirmed additionally by confocal imaging. Furthermore, a single dose IP injection into PCC deficient mice decreased the propionyl-/acetyl-carnitine (C3/C2) ratio toward the normal level. These results show that a cell penetrating peptide can deliver active multimeric enzyme into mitochondria in vitro, in situ, and in vivo and push the size limit of intracellular delivery achieved so far. Our results are promising for other mitochondria-specific deficiencies.

Publisher URL: http://doi.org/10.1128/MCB.00491-17

DOI: 10.1128/MCB.00491-17

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