Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Goedeke, Leigh, Shulman, Gerald I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
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
_version_ 1783686375570145280
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
work_keys_str_mv AT goedekeleigh therapeuticpotentialofmitochondrialuncouplersforthetreatmentofmetabolicassociatedfattyliverdiseaseandnash
AT shulmangeraldi therapeuticpotentialofmitochondrialuncouplersforthetreatmentofmetabolicassociatedfattyliverdiseaseandnash