TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM‐deficient cells

TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver... 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 MTSs 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Cellular and Molecular Medicine Wiley

TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM‐deficient cells

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Publisher
Wiley Subscription Services, Inc., A Wiley Company
Copyright
Copyright © 2018 John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
ISSN
1582-1838
eISSN
1582-4934
D.O.I.
10.1111/jcmm.13435
Publisher site
See Article on Publisher Site

Abstract

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 MTSs 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.

Journal

Journal of Cellular and Molecular MedicineWiley

Published: Jan 1, 2018

Keywords: ; ; ; ; ;

References

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