A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition

Abstract Mitochondria are involved in a variety of physiological and pathological processes. Ca2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca2+ overload into mitochondria in...

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Autores principales:	Naohiro Kon, Atsushi Satoh, Naoki Miyoshi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/862a9fb61a6b4d48934af82cecd9a49a
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spelling	oai:doaj.org-article:862a9fb61a6b4d48934af82cecd9a49a2021-12-02T16:06:33ZA small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition10.1038/s41598-017-03651-72045-2322https://doaj.org/article/862a9fb61a6b4d48934af82cecd9a49a2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03651-7https://doaj.org/toc/2045-2322Abstract Mitochondria are involved in a variety of physiological and pathological processes. Ca2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca2+ 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 Ca2+-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca2+-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 Ca2+ 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 Ca2+ uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca2+-overload into mitochondria.Naohiro KonAtsushi SatohNaoki MiyoshiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Naohiro Kon Atsushi Satoh Naoki Miyoshi A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition
description	Abstract Mitochondria are involved in a variety of physiological and pathological processes. Ca2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca2+ 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 Ca2+-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca2+-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 Ca2+ 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 Ca2+ uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca2+-overload into mitochondria.
format	article
author	Naohiro Kon Atsushi Satoh Naoki Miyoshi
author_facet	Naohiro Kon Atsushi Satoh Naoki Miyoshi
author_sort	Naohiro Kon
title	A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition
title_short	A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition
title_full	A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition
title_fullStr	A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition
title_full_unstemmed	A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition
title_sort	small-molecule ds44170716 inhibits ca2+-induced mitochondrial permeability transition
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/862a9fb61a6b4d48934af82cecd9a49a
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A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition

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