DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter

In cardiac myocytes, regulation of mitochondrial Ca 2+ is important for cellular signaling and cardiac contraction. Ca 2+ entry into the mitochondria is mediated by a highly selective Ca 2+ channel called the mitochondrial calcium uniporter, which consists of a pore-forming subunit MCU and regulator...

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Bibliographic Details
Published in:Cell death discovery 2017-07, Vol.3 (1), p.17045-17045, Article 17045
Main Authors: Kon, Naohiro, Murakoshi, Michiko, Isobe, Aya, Kagechika, Katsuji, Miyoshi, Naoki, Nagayama, Takahiro
Format: Article
Language:English
Subjects:
Apoptosis
Biochemistry
Biomedical and Life Sciences
Calcium (mitochondrial)
Calcium influx
Cardiomyocytes
Cell Biology
Cell Cycle Analysis
Contraction
Heart
Heart diseases
Heart rate
High-throughput screening
Life Sciences
Mitochondria
Muscle contraction
Myocytes
Regulatory subunits
Rodents
Stem Cells
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Summary:In cardiac myocytes, regulation of mitochondrial Ca 2+ is important for cellular signaling and cardiac contraction. Ca 2+ entry into the mitochondria is mediated by a highly selective Ca 2+ channel called the mitochondrial calcium uniporter, which consists of a pore-forming subunit MCU and regulatory subunits such as MICU1. Although pharmacological regulation of the mitochondrial Ca 2+ influx is a promising approach to controlling the cellular functions, a cell-permeable and specific inhibitor of the mitochondrial calcium uniporter has not yet been developed. Here, we identify a novel cell-permeable inhibitor of the uniporter by a high-throughput screening of 120 000 small-molecule compounds. In our study, DS16570511 dose-dependently inhibited serum-induced mitochondrial Ca 2+ influx in HEK293A cells with an IC 50 of 7  μ M. DS16570511 inhibited Ca 2+ uptake of isolated mitochondria from human cells, rat heart and pig heart. Overexpression of hMCU or hMICU1 in HEK293A cells increased mitochondrial Ca 2+ influx, and the increases were completely suppressed by the pretreatment with DS16570511. DS16570511 also blocks mitochondrial Ca 2+ overload in a Langendorff perfused beating rat heart. Interestingly, DS16570511 increased cardiac contractility without affecting heart rate in the perfused heart. These results show that DS16570511 is a novel cell-permeable inhibitor of the mitochondrial calcium uniporter and applicable for control of the cardiac functions.
ISSN:2058-7716
2058-7716
DOI:10.1038/cddiscovery.2017.45