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.
Highlights
Considering the central role of mitochondria in ATP production, it is not surprising that numerous diseases and disorders are associated with mitochondrial dysfunctions and mutations, including metabolic pathologies [1,2,3], neurodegenerative diseases [4], brain injuries [5], deafness [6], eyesight defects [7] and many more
These disorders can be classified into three groups: 1. diseases caused by mitochondrial DNA mutations; 2. diseases caused by mitochondrial mutations in nuclear DNA encoding mitochondrial proteins; 3. pathologies caused indirectly by mitochondria, in which mitochondrial dysfunction is correlated to the pathology or leads to its deterioration
We aimed to explore whether mitochondrial protein targeting via heterologous mitochondrial targeting sequence (MTS) could be used for the human methylmalonyl-coenzyme A (CoA) mutase (MCM) enzyme
Summary
Considering the central role of mitochondria in ATP production, it is not surprising that numerous diseases and disorders are associated with mitochondrial dysfunctions and mutations, including metabolic pathologies [1,2,3], neurodegenerative diseases [4], brain injuries [5], deafness [6], eyesight defects [7] and many more. These disorders can be classified into three groups: 1. The ability to target specific intracellular sublocalizations such as the nuclei, the mitochondria and lysosomes a 2017 The Authors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
