Bretscher Heidi, O'Connor Michael B
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
iScience. 2024 Dec 16;28(1):111611. doi: 10.1016/j.isci.2024.111611. eCollection 2025 Jan 17.
Maintaining metabolic homeostasis requires coordinated nutrient utilization between intracellular organelles and across multiple organ systems. Many organs rely heavily on mitochondria to generate (ATP) from glucose, or stored glycogen. Proteins required for ATP generation are encoded in both nuclear and mitochondrial DNA (mtDNA). We show that motoneuron to muscle signaling by the TGFβ/Activin family member Actβ positively regulates glycogen levels during development. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, loss of Actβ reduces levels of nuclearly encoded genes required for mtDNA replication, transcription, and translation and mtDNA levels. Direct RNAi knockdown of nuclearly encoded mtDNA expression factors in muscle also results in decreased glycogen stores. Lastly, expressing an activated form of the type I receptor Baboon in muscle restores both glycogen and mtDNA levels in mutants, thereby confirming a direct link between Actβ signaling, glycogen homeostasis, and mtDNA expression factors.
维持代谢稳态需要细胞内细胞器之间以及多个器官系统之间协调营养物质的利用。许多器官严重依赖线粒体从葡萄糖或储存的糖原中生成三磷酸腺苷（ATP）。ATP生成所需的蛋白质由核DNA和线粒体DNA（mtDNA）编码。我们发现，转化生长因子β/激活素家族成员激活素β（Actβ）介导的运动神经元向肌肉的信号传导在发育过程中正向调节糖原水平。值得注意的是，我们发现储存的糖原水平不受细胞质葡萄糖分解代谢改变的影响。相反，Actβ的缺失会降低mtDNA复制、转录和翻译以及mtDNA水平所需的核编码基因的水平。在肌肉中直接通过RNA干扰敲低核编码的mtDNA表达因子也会导致糖原储备减少。最后，在肌肉中表达I型受体狒狒的激活形式可恢复突变体中的糖原和mtDNA水平，从而证实Actβ信号传导、糖原稳态和mtDNA表达因子之间存在直接联系。
