Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress:: a novel mode of inter-organelle crosstalk
Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress:: a novel mode of inter-organelle crosstalk
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DOI：
10.1093/emboj/18.3.522
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发表时间：
1999-02-01
期刊：
影响因子：
11.4
通讯作者：
Avadhani, NG
中科院分区：
文献类型：
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作者：
Biswas, G;Adebanjo, OA;Avadhani, NG
我们研究了小鼠C2 C12心肌细胞在细胞应激过程中线粒体-核串扰的机制。为此，我们使用了溴化乙锭处理的线粒体DNA（mtDNA）含量降低的细胞或用已知的线粒体代谢抑制剂（包括羰基氰间氯苯腙（CCCP）、抗霉素、缬氨霉素和叠氮化物）处理的心肌细胞。遗传和代谢应激同样影响线粒体膜电位（Δ psi（m））和电子传递偶联的ATP合成，这也伴随着稳态胞质Ca 2+水平升高（[Ca 2 +]（i））。线粒体应激导致：（i）肌浆网ryanodine受体-1（RyR-1）表达增强，从而增强钙释放，以响应其调节剂咖啡因;（ii）增加的Ca 2 +-响应因子钙调磷酸酶水平，钙调神经磷酸酶依赖性NFATc（活化T细胞特异性核因子的胞浆对应物）和c-Jun N-末端激酶（JNK）依赖性ATF 2（iii）转录因子NF-κ B水平降低;和（iv）细胞色素氧化酶Vb（考克斯Vb）亚基基因的转录增强。这些细胞变化，包括稳态[Ca 2 +]（i）在含有接近正常mtDNA水平的遗传回复细胞中被标准化，我们认为，细胞核应激信号通过胞质[Ca 2 +]（i）变化发生，这可能是由于ATP和Ca 2+流出减少。我们的研究结果表明，线粒体应激信号影响各种细胞过程，除了线粒体膜生物合成。
We have investigated the mechanism of mitochondrial-nuclear crosstalk during cellular stress in mouse C2C12 myocytes, For this purpose, we used cells with reduced mitochondrial DNA (mtDNA) contents by ethidium bromide treatment or myocytes treated with known mitochondrial metabolic inhibitors, including carbonyl cyanide m-chlorophenylhydrazone (CCCP), antimycin, valinomycin and azide. Both genetic and metabolic stresses similarly affected mitochondrial membrane potential (Delta psi(m),) and electron transport-coupled ATP synthesis, which was also accompanied by an elevated steady-state cytosolic Ca2+ level ([Ca2+](i)). The mitochondrial stress resulted in: (i) an enhanced expression of the sarcoplasmic reticular ryanodine receptor-1 (RyR-1), hence potentiating the Ca2+ release in response to its modulator, caffeine; (ii) enhanced levels of Ca2+-responsive factors calineurin, calcineurin-dependent NFATc (cytosolic counterpart of activated T-cell-specific nuclear factor) and c-Jun N-terminal kinase (JNK)-dependent ATF2 (activated transcription factor 2); (iii) reduced levels of transcription factor, NF-KB; and (iv) enhanced transcription of cytochrome oxidase Vb (COX Vb) subunit gene, These cellular changes, including the steady-state [Ca2+](i) were normalized in genetically reverted cells which contain near-normal mtDNA levels, We propose that the mitochondria-to-nucleus stress signaling occurs through cytosolic [Ca2+](i) changes, which are likely to be due to reduced ATP and Ca2+ efflux. Our results indicate that the mitochondrial stress signal affects a variety of cellular processes, in addition to mitochondrial membrane biogenesis.