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A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition

Mitochondria are involved in a variety of physiological and pathological processes. Ca(2+) uptake is one of the important functions of the organelle for maintenance of cellular Ca(2+) homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca(2+) overload into mitochondria induc...

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Autores principales: Kon, Naohiro, Satoh, Atsushi, Miyoshi, Naoki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478606/
https://www.ncbi.nlm.nih.gov/pubmed/28634393
http://dx.doi.org/10.1038/s41598-017-03651-7
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author Kon, Naohiro
Satoh, Atsushi
Miyoshi, Naoki
author_facet Kon, Naohiro
Satoh, Atsushi
Miyoshi, Naoki
author_sort Kon, Naohiro
collection PubMed
description Mitochondria are involved in a variety of physiological and pathological processes. Ca(2+) uptake is one of the important functions of the organelle for maintenance of cellular Ca(2+) homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca(2+) overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT. Here we report upon a small-molecule compound DS44170716 that inhibits Ca(2+)-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca(2+)-induced death with a level of protection similar to cyclosporin A (CsA). The inhibitory mechanism of DS44170716 against MPT is independent on PPIF, a target of CsA. DS44170716 blocks Ca(2+) flux into the mitochondria by decreasing mitochondrial membrane potential, while potently inhibiting mitochondrial complex III activities and weakly inhibiting complex IV and V activities. Similarly, complex III inhibitor antimycin A, complex IV inhibitor KCN or complex V inhibitor oligomycin inhibits Ca(2+) uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca(2+)-overload into mitochondria.
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spelling pubmed-54786062017-06-23 A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition Kon, Naohiro Satoh, Atsushi Miyoshi, Naoki Sci Rep Article Mitochondria are involved in a variety of physiological and pathological processes. Ca(2+) uptake is one of the important functions of the organelle for maintenance of cellular Ca(2+) homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca(2+) overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT. Here we report upon a small-molecule compound DS44170716 that inhibits Ca(2+)-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca(2+)-induced death with a level of protection similar to cyclosporin A (CsA). The inhibitory mechanism of DS44170716 against MPT is independent on PPIF, a target of CsA. DS44170716 blocks Ca(2+) flux into the mitochondria by decreasing mitochondrial membrane potential, while potently inhibiting mitochondrial complex III activities and weakly inhibiting complex IV and V activities. Similarly, complex III inhibitor antimycin A, complex IV inhibitor KCN or complex V inhibitor oligomycin inhibits Ca(2+) uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca(2+)-overload into mitochondria. Nature Publishing Group UK 2017-06-20 /pmc/articles/PMC5478606/ /pubmed/28634393 http://dx.doi.org/10.1038/s41598-017-03651-7 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kon, Naohiro
Satoh, Atsushi
Miyoshi, Naoki
A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition
title A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition
title_full A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition
title_fullStr A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition
title_full_unstemmed A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition
title_short A small-molecule DS44170716 inhibits Ca(2+)-induced mitochondrial permeability transition
title_sort small-molecule ds44170716 inhibits ca(2+)-induced mitochondrial permeability transition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478606/
https://www.ncbi.nlm.nih.gov/pubmed/28634393
http://dx.doi.org/10.1038/s41598-017-03651-7
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