Abstract
Mitochondrial cytopathies are a heterogeneous group of systemic disorders caused by mutations in mitochondrial or nuclear genome. The review presents some data on pathogenic mutations in mitochondrial DNA leading to the imbalance in the oxidation phosphorylation processes and energy metabolism in the cells and eventually to the development of mitochondrial cytopathy. The pathways of medicated correction are examined, which are aimed at obtaining optimal energy efficiency of mitochondria with impaired functions, increase of the efficiency of energy metabolism in the tissues, as well as prevention of mitochondrial membrane damage by free radicals using antioxidants and membrane protectors. A conclusion is drawn on the inefficiency of currently used therapeutic strategies and the necessity of new approaches, which can be gene therapy of mitochondrial diseases. Some modern methods for gene defects correction, capable of restoring or removing the damaged gene, expressing full gene product, or blocking the mutant or strange genes work are analyzed. It is shown that the described approaches to the gene therapy of human mitochondrial diseases demand the introduction of foreign sequences into nuclear or mitochondrial genome of a living person, which completely excludes their practical application because of the uncertainty of the outcome. A perspective approach in solving this problem may be a creation of a system allowing the correction of defect genes without introducing synthetic nucleotides into the human genome. Phenotypic selection combined with a capacity of homologous recombination, artificially imparted to mitochondria of yeast Yarrowia lipolytica, allows for replication of intact human mitochondrial DNA in yeast mitochondria, supporting a full-size native human mitochondrial DNA in the yeast cells and eliminating pathogenic mutations by means of standard sitedirected PCR mutagenesis. After the correction in the Y. lipolytica cells, copies of mitochondrial DNA of an individual patient may be returned to him using the transfection of mesenchymal stromal cells followed by selection of transfectants grown in minimal culture media, in which the cells with higher respiratory mitochondrial activity will gain the advantage.
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Original Russian Text © V.V. Teplova, Yu.I. Deryabina, E.P. Isakova, 2017, published in Biologicheskie Membrany, 2017, Vol. 34, No. 2, pp. 91–108.
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Teplova, V.V., Deryabina, Y.I. & Isakova, E.P. Mitochondrial cytopathies: Their causes and correction pathways. Biochem. Moscow Suppl. Ser. A 11, 87–102 (2017). https://doi.org/10.1134/S1990747817020088
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DOI: https://doi.org/10.1134/S1990747817020088