Department of Physiology, UT Southwestern Medical Center, Dallas, TX, USA.
Nat Metab. 2021 Sep;3(9):1259-1274. doi: 10.1038/s42255-021-00450-3. Epub 2021 Sep 20.
Changes in maternal diet and metabolic defects in mothers can profoundly affect health and disease in their progeny. However, the biochemical mechanisms that induce the initial reprogramming events at the cellular level have remained largely unknown owing to limitations in obtaining pure populations of quiescent oocytes. Here, we show that the precocious onset of mitochondrial respiratory quiescence causes a reprogramming of progeny metabolic state. The premature onset of mitochondrial respiratory quiescence drives the lowering of Drosophila oocyte NAD levels. NAD depletion in the oocyte leads to reduced methionine cycle production of the methyl donor S-adenosylmethionine in embryos and lower levels of histone H3 lysine 27 trimethylation, resulting in enhanced intestinal lipid metabolism in progeny. In addition, we show that triggering cellular quiescence in mammalian cells and chemotherapy-resistant human cancer cell models induces cellular reprogramming events identical to those seen in Drosophila, suggesting a conserved metabolic mechanism in systems reliant on quiescent cells.
母体饮食和母体代谢缺陷的变化可深刻影响后代的健康和疾病。然而，由于难以获得纯品静止卵母细胞，细胞水平初始重编程事件的生化机制在很大程度上仍不清楚。本研究显示，线粒体呼吸静止的过早出现导致了后代代谢状态的重编程。线粒体呼吸静止的过早出现驱动了果蝇卵母细胞 NAD 水平的降低。卵母细胞中的 NAD 耗竭导致甲基供体 S-腺苷甲硫氨酸的蛋氨酸循环生成减少，胚胎中的组蛋白 H3 赖氨酸 27 三甲基化水平降低，导致后代肠道脂质代谢增强。此外，本研究还表明，在哺乳动物细胞和化疗耐药的人类癌细胞模型中引发细胞静止会诱导与在果蝇中观察到的相同的细胞重编程事件，这表明在依赖静止细胞的系统中存在保守的代谢机制。
