PDF(Pubmed)
Abstract：
Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations in the TAFAZZIN gene, which is responsible for the remodeling of the phospholipid cardiolipin (CL), lead to abnormalities in mitochondrial membrane, including alteration of mature CL acyl composition and the presence of monolysocardiolipin (MLCL). The dramatic increase in the MLCL/CL ratio is the hallmark of patients with BTHS, which is associated with mitochondrial bioenergetics dysfunction and altered membrane ultrastructure. There are currently no specific therapies for BTHS. Here, we showed that cardiac mitochondria isolated from TAFAZZIN knockdown (TazKD) mice presented abnormal ultrastructural membrane morphology, accumulation of vacuoles, pro-fission conditions and defective mitophagy. Interestingly, we found that in vivo treatment of TazKD mice with a CL-targeted small peptide (named SS-31) was able to restore mitochondrial morphology in tafazzin-deficient heart by affecting specific proteins involved in dynamic process and mitophagy. This agrees with our previous data showing an improvement in mitochondrial respiratory efficiency associated with increased supercomplex organization in TazKD mice under the same pharmacological treatment. Taken together our findings confirm the beneficial effect of SS-31 in the amelioration of tafazzin-deficient dysfunctional mitochondria in a BTHS animal model.
摘要：
巴特综合征（BTHS）是一种致命的罕见遗传疾病，导致心脏功能障碍，严重的骨骼肌无力，免疫问题和生长延迟。TAFAZZIN基因突变,负责磷脂心磷脂（CL）的重塑，导致线粒体膜异常，包括成熟CL酰基组成的改变和单心磷脂(MLCL)的存在。MLCL/CL比率的急剧增加是BTHS患者的标志，与线粒体生物能学功能障碍和膜超微结构改变有关。目前尚无针对BTHS的特定疗法。这里,我们发现，从TAFAZZIN敲低（TazKD）小鼠分离的心脏线粒体呈现异常的超微结构膜形态，空泡的积累，亲裂变条件和线粒体自噬缺陷。有趣的是,我们发现,用CL靶向的小肽(命名为SS-31)对Tazzin缺陷型心脏的体内治疗能够通过影响参与动态过程和线粒体自噬的特定蛋白来恢复线粒体形态.这与我们先前的数据一致，该数据显示，在相同的药物治疗下，TazKD小鼠的线粒体呼吸效率与超复合物组织增加相关。总而言之，我们的发现证实了SS-31在BTHS动物模型中改善tafazzin缺陷的功能失调线粒体的有益作用。
