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KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041391/ https://www.ncbi.nlm.nih.gov/pubmed/30026729 http://dx.doi.org/10.3389/fneur.2018.00552 |
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author | Seo, Kang-Sik Kim, Jin-Hwan Min, Ki-Nam Moon, Jeong-A Roh, Tae-Chul Lee, Mi-Jung Lee, Kang-Woo Min, Ji-Eun Lee, Young-Mock |
author_facet | Seo, Kang-Sik Kim, Jin-Hwan Min, Ki-Nam Moon, Jeong-A Roh, Tae-Chul Lee, Mi-Jung Lee, Kang-Woo Min, Ji-Eun Lee, Young-Mock |
author_sort | Seo, Kang-Sik |
collection | PubMed |
description | Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ10, vitamins, and nutrients, but no treatment with proven efficacy is currently available. In this study, we investigated the effects of a novel NAD(+) modulator, KL1333, in human fibroblasts derived from a human patient with MELAS. KL1333 is an orally available, small organic molecule that reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate, resulting in increases in intracellular NAD(+) levels via NADH oxidation. To elucidate the mechanism of action of KL1333, we used C2C12 myoblasts, L6 myoblasts, and MELAS fibroblasts. Elevated NAD(+) levels induced by KL1333 triggered the activation of SIRT1 and AMPK, and subsequently activated PGC-1α in these cells. In MELAS fibroblasts, KL1333 increased ATP levels and decreased lactate and ROS levels, which are often dysregulated in this disease. In addition, mitochondrial functional analyses revealed that KL1333 increased mitochondrial mass, membrane potential, and oxidative capacity. These results indicate that KL1333 improves mitochondrial biogenesis and function, and thus represents a promising therapeutic agent for the treatment of MELAS. |
format | Online Article Text |
id | pubmed-6041391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60413912018-07-19 KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts Seo, Kang-Sik Kim, Jin-Hwan Min, Ki-Nam Moon, Jeong-A Roh, Tae-Chul Lee, Mi-Jung Lee, Kang-Woo Min, Ji-Eun Lee, Young-Mock Front Neurol Neurology Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ10, vitamins, and nutrients, but no treatment with proven efficacy is currently available. In this study, we investigated the effects of a novel NAD(+) modulator, KL1333, in human fibroblasts derived from a human patient with MELAS. KL1333 is an orally available, small organic molecule that reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate, resulting in increases in intracellular NAD(+) levels via NADH oxidation. To elucidate the mechanism of action of KL1333, we used C2C12 myoblasts, L6 myoblasts, and MELAS fibroblasts. Elevated NAD(+) levels induced by KL1333 triggered the activation of SIRT1 and AMPK, and subsequently activated PGC-1α in these cells. In MELAS fibroblasts, KL1333 increased ATP levels and decreased lactate and ROS levels, which are often dysregulated in this disease. In addition, mitochondrial functional analyses revealed that KL1333 increased mitochondrial mass, membrane potential, and oxidative capacity. These results indicate that KL1333 improves mitochondrial biogenesis and function, and thus represents a promising therapeutic agent for the treatment of MELAS. Frontiers Media S.A. 2018-07-05 /pmc/articles/PMC6041391/ /pubmed/30026729 http://dx.doi.org/10.3389/fneur.2018.00552 Text en Copyright © 2018 Seo, Kim, Min, Moon, Roh, Lee, Lee, Min and Lee. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neurology Seo, Kang-Sik Kim, Jin-Hwan Min, Ki-Nam Moon, Jeong-A Roh, Tae-Chul Lee, Mi-Jung Lee, Kang-Woo Min, Ji-Eun Lee, Young-Mock KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts |
title | KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts |
title_full | KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts |
title_fullStr | KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts |
title_full_unstemmed | KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts |
title_short | KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts |
title_sort | kl1333, a novel nad(+) modulator, improves energy metabolism and mitochondrial dysfunction in melas fibroblasts |
topic | Neurology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041391/ https://www.ncbi.nlm.nih.gov/pubmed/30026729 http://dx.doi.org/10.3389/fneur.2018.00552 |
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