KDM5-mediated transcriptional activation of ribosomal protein genes alters translation efficiency to regulate mitochondrial metabolism

Genes encoding the KDM5 family of transcriptional regulators are disrupted in individuals with intellectual disability (ID). To understand the link between KDM5 and ID, we generated five Drosophila strains harboring missense alleles analogous to those observed in patients. These alleles showed effects on neuroanatomical development, cognition, and other behaviors, in addition to a transcriptional signature that included the downregulation of many ribosomal protein genes. A similar transcriptional profile was observed in KDM5C knockout human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs), suggesting a conserved role for KDM5 proteins in regulating ribosomal protein genes. Quantifying changes to the translatome caused by reduced KDM5 in Drosophila neurons, we find that the translation of mRNAs required for mitochondrial activity was particularly affected. Altered mitochondrial activity was confirmed through metabolomic studies that revealed decreased citric acid cycle activity. KDM5 therefore plays a key role in maintaining mitochondrial function that, when altered, could contribute to cognitive and behavioral phenotypes.

在智力障碍（intellectual disability，ID）患者体内，编码KDM5家族转录调控因子的基因发生功能破坏。为阐明KDM5与ID之间的关联机制，我们构建了5株携带与患者体内致病变异类型相似的错义等位基因的果蝇品系。这些错义等位基因不仅会导致大量核糖体蛋白基因转录下调，还会对果蝇的神经解剖发育、认知功能及其他行为产生显著影响。在由诱导多能干细胞（induced pluripotent stem cells, iPSCs）分化获得的KDM5C基因敲除人源谷氨酸能神经元中，同样观测到相似的转录谱特征，这提示KDM5家族蛋白在调控核糖体蛋白基因表达方面具有保守功能。通过定量分析果蝇神经元中KDM5表达下调引发的翻译组（translatome）变化，我们发现线粒体功能相关mRNA的翻译过程受到尤为显著的影响。代谢组学研究进一步验证了线粒体功能异常：该研究揭示三羧酸循环活性降低。综上，KDM5在维持线粒体功能方面发挥关键作用，当其功能异常时，可能会导致认知与行为表型改变。