Rapamycin enhances survival in a Drosophila model of mitochondrial disease.
Rapamycin enhances survival in a Drosophila model of mitochondrial disease.
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DOI：
10.18632/oncotarget.12560
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发表时间：
2016-12-06
期刊：
影响因子：
--
通讯作者：
Kaeberlein M
中科院分区：
文献类型：
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作者：
Wang A;Mouser J;Pitt J;Promislow D;Kaeberlein M
儿科线粒体疾病是由线粒体功能缺陷引起的一类破坏性疾病。Leigh综合征（LS）是这些疾病中最常见的，症状通常在出生后第一年内出现，并迅速进展直至死亡，通常在6-7岁。我们的实验室最近表明，雷帕霉素（TOR）的机制靶点的遗传抑制挽救了线粒体功能缺陷的酵母突变体的短寿命，并且通过给予雷帕霉素对TOR的药理学抑制显著挽救了LS小鼠模型中的寿命缩短，神经症状和神经变性。然而，TOR抑制发挥这些作用的机制，以及这些作用可以扩展到其他线粒体缺陷模型的程度尚不清楚。在这里，我们探测TOR抑制在果蝇模型的复杂的I缺陷的影响。用雷帕霉素治疗有力地抑制了该LS模型中的寿命缺陷，而不影响行为表型。有趣的是，这种响应于TOR抑制的寿命增加以不依赖于自噬的方式发生。此外，我们确定了一个脂肪储存缺陷的ND 2突变苍蝇，是由雷帕霉素拯救，支持雷帕霉素发挥其作用的线粒体疾病在这些动物通过改变代谢的模型。
Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS. However, the mechanism by which TOR inhibition exerts these effects, and the extent to which these effects can extend to other models of mitochondrial deficiency, are unknown. Here, we probe the effects of TOR inhibition in a Drosophila model of complex I deficiency. Treatment with rapamycin robustly suppresses the lifespan defect in this model of LS, without affecting behavioral phenotypes. Interestingly, this increased lifespan in response to TOR inhibition occurs in an autophagy-independent manner. Further, we identify a fat storage defect in the ND2 mutant flies that is rescued by rapamycin, supporting a model that rapamycin exerts its effects on mitochondrial disease in these animals by altering metabolism.