NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter

Thu, Vũ Thị; Kim, Hyoung Kyu; Long, Lê Thanh; Lee, Sungryul; Hanh, Tran My; Ko, Tae Hee; Heo, Hye-Jin; Kim, Nari; Kim, Soon Ha; Ko, Kyung Soo; Rhee, Byoung Doo; Han, Jin

doi:10.1093/cvr/cvs122

Cited by 64 publications

(68 citation statements)

References 42 publications

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“…The NecroX series of small molecules is known to exhibit cytoprotective and anti-oxidant activities in several cell types (Choi et al, 2010;Kim et al, 2010;Park et al, 2012;Thu et al, 2012). Of the NecroX series, NecroX-7 is a clinical candidate in preclinical settings and is structurally similar to NecroX-2 and -5 .…”

Section: Introductionmentioning

confidence: 99%

A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κB activity and c-Fos expression

et al. 2012

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Section: Introductionmentioning

confidence: 99%

A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κB activity and c-Fos expression

et al. 2012

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“…Serum deprivation-induced p17 formation was significantly reduced by treatment of STAT3 KO cells with NCX5 (Fig. 8C), a cell permeable antioxidant that localizes mostly in the mitochondria [32]. Treatment of STAT3 KO MEF with GME, which undergoes hydrolysis by intracellular esterases to release glutathione [33], also attenuated p17 formation with serum deprivation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability

et al. 2014

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STAT3 has been implicated in mitochondrial function; however, the physiological relevance of this action is not established. Here we studied the importance of STAT3 to the cellular response to stimuli, TNFα and serum deprivation, which increase mitochondrial reactive oxygen species (ROS) formation. Experiments were performed using wild type (WT) and STAT3 knockout (KO) mouse embryonic fibroblasts (MEF). Both WT and STAT3 KO MEF expressed similar levels of tumor necrosis factor receptor 1 (TNFR1) and exhibited comparable IκBα degradation with TNFα. However, in the absence of STAT3 nuclear accumulation of NFκB p65 with TNFα was attenuated and induction of the survival protein c-FLIPL was eliminated. Nonetheless, WT MEF were more sensitive to TNFα-induced death which was attributed to necrosis. Deletion of STAT3 decreased ROS formation induced by TNFα and serum deprivation. STAT3 deletion was associated with lower levels of complex I and rates of respiration. Relative to WT cells, mitochondria of STAT3 KO cells released significantly more cytochrome c in response to oxidative stress and had greater caspase 3 cleavage due to serum deprivation. Our findings are consistent with STAT3 being important for mitochondrial function and cell viability by ensuring mitochondrial integrity and the expression of pro-survival genes.

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“…24 NecroX-5, one of the derivatives of the reactive oxygen species scavenger NecroX series compounds, was found to attenuate Ca 2+ accumulation in cultured myocytes. 25 And it was demonstrated that antibiotic minocycline inhibits Ca 2+ uptake in isolated rat liver mitochondria. 26 Original findings of these compounds did not indicate them as being specific inhibitors of the uniporter, and the compounds have additional biochemical actions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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In cardiac myocytes, regulation of mitochondrial Ca2+ is important for cellular signaling and cardiac contraction. Ca2+ entry into the mitochondria is mediated by a highly selective Ca2+ 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 Ca2+ 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 Ca2+ influx in HEK293A cells with an IC50 of 7 μM. DS16570511 inhibited Ca2+ uptake of isolated mitochondria from human cells, rat heart and pig heart. Overexpression of hMCU or hMICU1 in HEK293A cells increased mitochondrial Ca2+ influx, and the increases were completely suppressed by the pretreatment with DS16570511. DS16570511 also blocks mitochondrial Ca2+ 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.

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NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter

Abstract: These findings suggest that NecroX-5 may act as a mitochondrial Ca(2+) uniporter inhibitor to protect cardiac mitochondria against HR damage.

Cited by 64 publications

References 42 publications

A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κB activity and c-Fos expression

A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κB activity and c-Fos expression

Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability

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

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