Zulian Alessandra, Schiavone Marco, Giorgio Valentina, Bernardi Paolo
CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Padova, Italy.
CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Padova, Italy.
Pharmacol Res. 2016 Nov;113(Pt A):563-573. doi: 10.1016/j.phrs.2016.09.043. Epub 2016 Sep 30.
The hypothesis that mitochondrial dysfunction can be a general mechanism for cell death in muscle diseases is 40 years old. The key elements of the proposed pathogenetic sequence (cytosolic Ca overload followed by excess mitochondrial Ca uptake, functional and then structural damage of mitochondria, energy shortage, worsened elevation of cytosolic Ca levels, hypercontracture of muscle fibers, cell necrosis) have been confirmed in amazing detail by subsequent work in a variety of models. The explicit implication of the hypothesis was that it "may provide the basis for a more rational treatment for some conditions even before their primary causes are known" (Wrogemann and Pena, 1976, Lancet, 1, 672-674). This prediction is being fulfilled, and the potential of mitochondria as pharmacological targets in muscle diseases may soon become a reality, particularly through inhibition of the mitochondrial permeability transition pore and its regulator cyclophilin D.
线粒体功能障碍可能是肌肉疾病中细胞死亡的普遍机制这一假说已有40年历史。随后在各种模型中的研究惊人地详细证实了所提出的发病序列的关键要素（胞质钙超载，随后线粒体钙摄取过多，线粒体功能和结构损伤，能量短缺，胞质钙水平进一步升高，肌肉纤维过度收缩，细胞坏死）。该假说明确指出，它“甚至在某些疾病的主要病因尚不清楚之前，就可能为更合理的治疗提供依据”（Wrogemann和Pena，1976年，《柳叶刀》，第1期，672 - 674页）。这一预测正在实现，线粒体作为肌肉疾病药物靶点的潜力可能很快成为现实，特别是通过抑制线粒体通透性转换孔及其调节因子亲环蛋白D。
