Brain and Mind Research Institute, Sydney Medical School, University of Sydney, NSW 2050, Australia.
Hum Mol Genet. 2013 Nov 15;22(22):4562-78. doi: 10.1093/hmg/ddt302. Epub 2013 Jun 25.
Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatment available. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found that cyclosporine A (CsA) reduces muscle degeneration at low dose and acts, at least in part, through a mitochondrial cyclophilin D, CYN-1. We thus hypothesized that CsA acts on mitochondrial permeability modulation through cyclophilin D inhibition. Mitochondrial patterns and dynamics were analyzed, which revealed dramatic mitochondrial fragmentation not only in dystrophic nematodes, but also in a zebrafish model for DMD. This abnormal mitochondrial fragmentation occurs before any obvious sign of degeneration can be detected. Moreover, we demonstrate that blocking/delaying mitochondrial fragmentation by knocking down the fission-promoting gene drp-1 reduces muscle degeneration and improves locomotion abilities of dystrophic nematodes. Further experiments revealed that cytochrome c is involved in muscle degeneration in C. elegans and seems to act, at least in part, through an interaction with the inositol trisphosphate receptor calcium channel, ITR-1. Altogether, our findings reveal that mitochondria play a key role in the early process of muscle degeneration and may be a target of choice for the design of novel therapeutics for DMD. In addition, our results provide the first indication in the nematode that (i) mitochondrial permeability transition can occur and (ii) cytochrome c can act in cell death.
杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的神经肌肉疾病。DMD 的亚细胞机制仍知之甚少，目前尚无有效的治疗方法。我们使用 DMD 的秀丽隐杆线虫模型作为药理学和遗传学工具，发现环孢素 A（CsA）在低剂量下可减少肌肉退化，至少部分作用机制是通过线粒体亲环素 D（CYN-1）。因此，我们假设 CsA 通过抑制亲环素 D 来作用于线粒体通透性调节。分析了线粒体的形态和动力学，结果显示不仅在营养不良的线虫中，而且在 DMD 的斑马鱼模型中，线粒体都出现了明显的碎片化。这种异常的线粒体碎片化发生在任何明显的退化迹象出现之前。此外，我们证明通过敲低促进分裂的基因 drp-1 阻断/延迟线粒体碎片化，可以减少肌肉退化并改善营养不良线虫的运动能力。进一步的实验表明，细胞色素 c 参与了秀丽隐杆线虫的肌肉退化，并且似乎至少部分通过与肌醇三磷酸受体钙通道 ITR-1 的相互作用起作用。总之，我们的研究结果表明，线粒体在肌肉退化的早期过程中起着关键作用，可能成为设计 DMD 新型治疗方法的选择目标。此外，我们的研究结果首次表明（i）线粒体通透性转换可能发生，（ii）细胞色素 c 可以在细胞死亡中发挥作用。
