Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy
Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy
复制标题
DOI：
10.1093/hmg/ddn355
复制
发表时间：
2009-01-15
影响因子：
3.5
通讯作者：
Westerblad, Hakan
中科院分区：
文献类型：
--
作者：
Aydin, Jan;Andersson, Daniel C.;Westerblad, Hakan
影响线粒体功能的基因突变通常会导致骨骼肌功能障碍。在这里，我们使用了小鼠与线粒体转录因子A（Tfam）的核基因的腹肌特异性中断，以研究细胞Ca 2+处理的变化是否是线粒体肌病肌肉功能障碍的机制的一部分。力的测量相结合的测量胞质Ca 2+，线粒体Ca 2+和膜电位和活性氧在完整的，成人肌纤维。结果显示，由于钙螯合蛋白-1的表达降低，Tfam KO肌肉中肌浆网（SR）Ca 2+储存能力降低。这导致收缩期间SR Ca 2+释放减少，因此Tfam KO中的力产生低于对照肌肉。此外，在Tfam KO细胞中没有氧化应激的迹象，而它们在重复收缩期间显示线粒体[Ca 2 +]增加。在终末期Tfam KO小鼠的肌细胞中，线粒体[Ca 2 +]在刺激结束后很长时间内仍保持升高，并且在亲环素D结合抑制剂环孢菌素A存在下增加较小。Tfam KO细胞的线粒体膜电位在重复收缩期间并未降低。总之，我们认为，所观察到的变化在Ca 2+处理的适应性反应与长期的不利影响。减少SR Ca 2+释放可能会降低ATP消耗，但也会导致肌肉无力。增加[Ca 2 +]（mit）将刺激线粒体代谢急剧，但也可能引发细胞损伤。
Genetic mutations that affect mitochondrial function often cause skeletal muscle dysfunction. Here, we used mice with skeletal-muscle-specific disruption of the nuclear gene for mitochondrial transcription factor A (Tfam) to study whether changes in cellular Ca2+ handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Force measurements were combined with measurements of cytosolic Ca2+, mitochondrial Ca2+ and membrane potential and reactive oxygen species in intact, adult muscle fibres. The results show reduced sarcoplasmic reticulum (SR) Ca2+ storage capacity in Tfam KO muscles due to a decreased expression of calsequestrin-1. This resulted in decreased SR Ca2+ release during contraction and hence lower force production in Tfam KO than in control muscles. Additionally, there were no signs of oxidative stress in Tfam KO cells, whereas they displayed increased mitochondrial [Ca2+] during repeated contractions. Mitochondrial [Ca2+] remained elevated long after the end of stimulation in muscle cells from terminally ill Tfam KO mice, and the increase was smaller in the presence of the cyclophilin D-binding inhibitor cyclosporin A. The mitochondrial membrane potential in Tfam KO cells did not decrease during repeated contractions. In conclusion, we suggest that the observed changes in Ca2+ handling are adaptive responses with long-term detrimental effects. Reduced SR Ca2+ release likely decreases ATP expenditure, but it also induces muscle weakness. Increased [Ca2+](mit) will stimulate mitochondrial metabolism acutely but may also trigger cell damage.