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Giordano 2021 Gene Ther

From Bioblast
Publications in the MiPMap
Giordano L, Aneja MK, Sommer N, Alebrahimdehkordi N, Seraji A, Weissmann N, Rudolph C, Plank C, Jacobs HT, Szibor M (2021) Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active.

Β» Gene Ther 29:655-64. PMID: 33664504 Open Access

Giordano Luca, Aneja Manish K, Sommer Natascha, Alebrahimdehkordi Nasim, Seraji Alireza, Weissmann Norbert, Rudolph Carsten, Plank Christian, Jacobs Howard T, Szibor Marten (2021) Gene Ther

Abstract: Plants and other organisms, but not insects or vertebrates, express the auxiliary respiratory enzyme alternative oxidase (AOX) that bypasses mitochondrial respiratory complexes III and/or IV when impaired. Persistent expression of AOX from Ciona intestinalis in mammalian models has previously been shown to be effective in alleviating some metabolic stresses produced by respiratory chain inhibition while exacerbating others. This implies that chronic AOX expression may modify or disrupt metabolic signaling processes necessary to orchestrate adaptive remodeling, suggesting that its potential therapeutic use may be confined to acute pathologies, where a single course of treatment would suffice. One possible route for administering AOX transiently is AOX-encoding nucleic acid constructs. Here we demonstrate that AOX-encoding chemically-modified RNA (cmRNA), sequence-optimized for expression in mammalian cells, was able to support AOX expression in immortalized mouse embryonic fibroblasts (iMEFs), human lung carcinoma cells (A549) and primary mouse pulmonary arterial smooth muscle cells (PASMCs). AOX protein was detectable as early as 3 h after transfection, had a half-life of ~4 days and was catalytically active, thus supporting respiration and protecting against respiratory inhibition. Our data demonstrate that AOX-encoding cmRNA optimized for use in mammalian cells represents a viable route to investigate and possibly treat mitochondrial respiratory disorders.

β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: DE Giessen Weissmann N, FI Helsinki Jacobs HT, DE Jena Szibor M

Labels: MiParea: Respiration, nDNA;cell genetics 

Organism: Mouse  Tissue;cell: Fibroblast  Preparation: Permeabilized cells, Intact cells 

Coupling state: LEAK, ROUTINE, OXPHOS  Pathway: N, S, CIV, ROX  HRR: Oxygraph-2k