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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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Detalles Bibliográficos
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
Descripción
Sumario: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.