Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Hum Mol Genet. 2018 Jan 1;27(1):95-106. doi: 10.1093/hmg/ddx387.
Fragile X Syndrome (FXS), the most prevalent form of inherited intellectual disability and the foremost monogenetic cause of autism, is caused by loss of expression of the FMR1 gene . Here, we show that dfmr1 modulates the global metabolome in Drosophila. Despite our previous discovery of increased brain insulin signaling, our results indicate that dfmr1 mutants have reduced carbohydrate and lipid stores and are hypersensitive to starvation stress. The observed metabolic deficits cannot be explained by feeding behavior, as we report that dfmr1 mutants are hyperphagic. Rather, our data identify dfmr1 as a regulator of mitochondrial function. We demonstrate that under supersaturating conditions, dfmr1 mutant mitochondria have significantly increased maximum electron transport system (ETS) capacity. Moreover, electron micrographs of indirect flight muscle reveal striking morphological changes in the dfmr1 mutant mitochondria. Taken together, our results illustrate the importance of dfmr1 for proper maintenance of nutrient homeostasis and mitochondrial function.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍形式，也是自闭症的首要单基因病因，由 FMR1 基因表达缺失引起。在这里，我们显示 dfmr1 可调节果蝇的整体代谢组。尽管我们之前发现大脑胰岛素信号增加，但我们的结果表明 dfmr1 突变体的碳水化合物和脂质储存减少，对饥饿应激敏感。观察到的代谢缺陷不能用进食行为来解释，因为我们报告 dfmr1 突变体是多食的。相反，我们的数据表明 dfmr1 是线粒体功能的调节剂。我们证明在过饱和条件下，dfmr1 突变体的线粒体具有显著增加的最大电子传递系统（ETS）容量。此外，间接飞行肌的电子显微镜照片显示 dfmr1 突变体线粒体的形态发生了明显变化。总之，我们的结果说明了 dfmr1 对于维持营养稳态和线粒体功能的重要性。
