Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.

真核细胞通过依赖于细胞质翻译与线粒体翻译的多种机制维持蛋白质稳态（proteostasis）。影响细胞质翻译的遗传缺陷会扰乱突触发育与神经传递，且是脆性X综合征（Fragile X syndrome）等神经发育障碍的致病诱因。与之相反，几乎尚无证据表明，以线粒体蛋白质翻译和/或降解形式存在的线粒体蛋白质稳态，是突触发育与功能所必需的。本研究聚焦于在可引发神经发育障碍的复发性拷贝数变异——22q11.2微缺失综合征（22q11.2 microdeletion syndrome）——中发生缺失的两个基因。本研究证实，位于该微缺失片段内的SLC25A1与MRPL40这两个基因，其编码产物定位于线粒体，二者存在相互作用，且对线粒体核糖体完整性与蛋白质稳态至关重要。我们的果蝇（Drosophila）实验表明，线粒体核糖体功能对于突触神经发育、突触功能与动物行为均不可或缺。我们提出，由遗传或环境因素引发的线粒体蛋白质稳态失调，是神经发育障碍的一种致病机制。