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Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH
BACKGROUND: Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity conce...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085597/ https://www.ncbi.nlm.nih.gov/pubmed/33545391 http://dx.doi.org/10.1016/j.molmet.2021.101178 |
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author | Goedeke, Leigh Shulman, Gerald I. |
author_facet | Goedeke, Leigh Shulman, Gerald I. |
author_sort | Goedeke, Leigh |
collection | PubMed |
description | BACKGROUND: Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases. SCOPE OF REVIEW: In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis (NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic. MAJOR CONCLUSIONS: Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns. |
format | Online Article Text |
id | pubmed-8085597 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-80855972021-05-11 Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH Goedeke, Leigh Shulman, Gerald I. Mol Metab Review BACKGROUND: Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases. SCOPE OF REVIEW: In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis (NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic. MAJOR CONCLUSIONS: Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns. Elsevier 2021-02-03 /pmc/articles/PMC8085597/ /pubmed/33545391 http://dx.doi.org/10.1016/j.molmet.2021.101178 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Review Goedeke, Leigh Shulman, Gerald I. Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH |
title | Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH |
title_full | Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH |
title_fullStr | Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH |
title_full_unstemmed | Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH |
title_short | Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH |
title_sort | therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and nash |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085597/ https://www.ncbi.nlm.nih.gov/pubmed/33545391 http://dx.doi.org/10.1016/j.molmet.2021.101178 |
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