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

Ye Tian¹  Bin Li¹  Wen-Zhen Shi¹  Ming-Ze Chang¹  Ge-Juan Zhang¹  Zheng-Li Di¹ 

[1]Department of Neurology, Xi’an Central Hospital, Xi’an Jiaotong University School of Medicine, Xi’an 710003, Shaanxi, China

[2] E-Mails:

关键词: stroke;    Drp-1;    calcium;    mitochondria;    endoplasmic reticulum;   

DOI  :  10.3390/ijms15023172

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland