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TAT ‐ MTS ‐ MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM ‐deficient cells
Author(s) -
ErlichHadad Tal,
Hadad Rita,
Feldman Anat,
Greif Hagar,
Lictenstein Michal,
LorberboumGalski Haya
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13435
Subject(s) - mitochondrion , fusion protein , biochemistry , biology , mitochondrial fusion , microbiology and biotechnology , gene , mitochondrial dna , recombinant dna
Methylmalonic aciduria ( MMA ) is a disorder of organic acid metabolism resulting from a functional defect of the mitochondrial enzyme, methylmalonyl‐CoA mutase ( MCM ). The main treatments for MMA patients are dietary restriction of propiogenic amino acids and carnitine supplementation. Liver or combined liver/kidney transplantation has been used to treat those with the most severe clinical manifestations. Thus, therapies are necessary to help improve quality of life and prevent liver, renal and neurological complications. Previously, we successfully used the TAT ‐ MTS ‐Protein approach for replacing a number of mitochondrial‐mutated proteins. In this targeted system, TAT , an 11 a.a peptide, which rapidly and efficiently can cross biological membranes, is fused to a mitochondrial targeting sequence ( MTS ), followed by the mitochondrial mature protein which sends the protein into the mitochondria. In the mitochondria, the TAT ‐ MTS is cleaved off and the native protein integrates into its natural complexes and is fully functional. In this study, we used heterologous MTS s of human, nuclear‐encoded mitochondrial proteins, to target the human MCM protein into the mitochondria. All fusion proteins reached the mitochondria and successfully underwent processing. Treatment of MMA patient fibroblasts with these fusion proteins restored mitochondrial activity such as ATP production, mitochondrial membrane potential and oxygen consumption, indicating the importance of mitochondrial function in this disease. Treatment with the fusion proteins enhanced cell viability and most importantly reduced MMA levels. Treatment also enhanced albumin and urea secretion in a CRISPR /Cas9‐engineered HepG2 MUT (‐/‐) liver cell line. Therefore, we suggest using this TAT ‐ MTS ‐Protein approach for the treatment of MMA .

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