FAM134B-Mediated ER-Phagy in Mg2+-Free Solution-Induced Mitochondrial Calcium Homeostasis and Cell Death in Epileptic Hippocampal Neurons

被引:15
作者
Wang, Cui [1 ]
Li, Yujuan [2 ]
Li, Yingjiao [2 ]
Du, Liyuan [2 ]
Zhang, Jingyu [1 ]
Li, Nan [1 ]
Hu, Xiaomei [1 ]
Zhang, Wenjing [1 ]
Xie, Nanchang [2 ]
Ming, Liang [1 ]
机构
[1] Zhengzhou Univ, Dept Clin Lab, Affiliated Hosp 1, Zhengzhou 450052, Peoples R China
[2] Zhengzhou Univ, Dept Neurol, Affiliated Hosp 1, Zhengzhou 450052, Peoples R China
基金
中国国家自然科学基金;
关键词
FAM134B; ER-phagy; MAMs; Epilepsy; Mitochondrial calcium homeostasis; ENDOPLASMIC-RETICULUM; CA2+; AUTOPHAGY;
D O I
10.1007/s11064-021-03389-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) regulate calcium (Ca2+) homeostasis via Ca2+ transport-related proteins such as inositol-1,4,5-triphosphate receptor (IP3R). FAM134B-mediated ER-phagy plays an important role in ER homeostasis. However, it remains unknown whether FAM134B-mediated ER-phagy affects mitochondrial Ca2+ homeostasis and cell death through MAMs. In this study, we demonstrated that colocalization degree of FAM134B with LC3 and the LC3-II/LC3-I ratio were elevated in the hippocampal neuronal culture (HNC) model of acquired epilepsy (AE), which indicate an increased level of autophagy. In this model, FAM134B overexpression enhanced ER-phagy, while FAM134B downregulation had the opposite effect. Additionally, FAM134B overexpression significantly reversed the increases in IP3R expression and mitochondrial Ca2+ concentration and the decrease in the ER Ca2+ concentration in this model. FAM134B overexpression also ameliorated the AE-induced ultrastructural damage in neuronal mitochondria, decrease in mitochondrial membrane potential (mMP), cytochrome c (CytC) release and caspase-3 activation, while FAM134B downregulation induced the opposite effects. Altogether, our data indicate that FAM134B-mediated ER-phagy can attenuate AE-induced neuronal apoptosis, possibly by modulating the IP3R in MAMs to alter Ca2+ exchange between ER and mitochondria and thus inhibit mitochondrial structural damage, a decrease in mMP, release of CytC and mitochondrial apoptosis.
引用
收藏
页码:2485 / 2494
页数:10
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