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Int. J. Mol. Sci. 2014, 15(2), 3172-3185; doi:10.3390/ijms15023172
Article

Dynamin-Related Protein 1 Inhibitors Protect against Ischemic Toxicity through Attenuating Mitochondrial Ca2+ Uptake from Endoplasmic Reticulum Store in PC12 Cells

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Received: 7 January 2014; in revised form: 25 January 2014 / Accepted: 27 January 2014 / Published: 21 February 2014
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Abstract: Intracellular calcium homeostasis disorder and mitochondrial dysfunction are involved in many acute and chronic brain diseases, including ischemic brain injury. An imbalance in mitochondrial fission and fusion is one of the most important structural abnormalities found in a large number of mitochondrial dysfunction related diseases. Here, we investigated the effects of mitochondrial division inhibitor A (mdivi A) and mdivi B, two small molecule inhibitors of mitochondrial fission protein dunamin-related protein 1 (Drp-1), in neuronal injury induced by oxygen-glucose deprivation (OGD) in PC12 cells. We found that mdivi A and mdivi B inhibited OGD-induced neuronal injury through attenuating apoptotic cell death. These two inhibitors also preserved mitochondrial function, as evidenced by reduced reactive oxygen species (ROS) generation and cytochrome c release, as well as prevented loss of mitochondrial membrane potential (MMP). Moreover, mdivi A and mdivi B significantly suppressed mitochondrial Ca2+ uptake, but had no effect on cytoplasmic Ca2+ after OGD injury. The results of calcium imaging and immunofluorescence staining showed that Drp-1 inhibitors attenuated endoplasmic reticulum (ER) Ca2+ release and prevented ER morphological changes induced by OGD. These results demonstrate that Drp-1 inhibitors protect against ischemic neuronal injury through inhibiting mitochondrial Ca2+ uptake from the ER store and attenuating mitochondrial dysfunction.
Keywords: stroke; Drp-1; calcium; mitochondria; endoplasmic reticulum stroke; Drp-1; calcium; mitochondria; endoplasmic reticulum
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Tian, Y.; Li, B.; Shi, W.-Z.; Chang, M.-Z.; Zhang, G.-J.; Di, Z.-L.; Liu, Y. Dynamin-Related Protein 1 Inhibitors Protect against Ischemic Toxicity through Attenuating Mitochondrial Ca2+ Uptake from Endoplasmic Reticulum Store in PC12 Cells. Int. J. Mol. Sci. 2014, 15, 3172-3185.

AMA Style

Tian Y, Li B, Shi W-Z, Chang M-Z, Zhang G-J, Di Z-L, Liu Y. Dynamin-Related Protein 1 Inhibitors Protect against Ischemic Toxicity through Attenuating Mitochondrial Ca2+ Uptake from Endoplasmic Reticulum Store in PC12 Cells. International Journal of Molecular Sciences. 2014; 15(2):3172-3185.

Chicago/Turabian Style

Tian, Ye; Li, Bin; Shi, Wen-Zhen; Chang, Ming-Ze; Zhang, Ge-Juan; Di, Zheng-Li; Liu, Yong. 2014. "Dynamin-Related Protein 1 Inhibitors Protect against Ischemic Toxicity through Attenuating Mitochondrial Ca2+ Uptake from Endoplasmic Reticulum Store in PC12 Cells." Int. J. Mol. Sci. 15, no. 2: 3172-3185.



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