Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1^−/y mouse have a mitochondrial inner membrane leak contributing to a “leak metabolism.” In human Fragile X syndrome (FXS) fibroblasts and in Fmr1^−/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

编码脆性 X 型智力低下蛋白 (FMRP)的基因 ( Fmr1 )的缺失导致 mRNA 翻译增加和突触发育异常。我们发现Fmr1 ^{- / y}小鼠的神经元有线粒体内膜泄漏，导致“泄漏代谢”。在人类脆性 X 综合征 (FXS) 成纤维细胞和Fmr1 ^{-/ y}小鼠神经元，通过轻度消耗其 c 亚基或药理学抑制来关闭 ATP 合酶泄漏通道，使刺激诱导和组成型 mRNA 翻译率正常化，降低乳酸和关键糖酵解和三羧酸 (TCA) 循环酶水平，并触发突触成熟. FMRP 通过刺激依赖性 ATP 合酶 β 亚基翻译调节野生型 (WT) 中的泄漏闭合，但不调节 FX 突触；这增加了 ATP 合酶与其 c 亚基的比率，从而提高了 ATP 生产效率和突触生长。相比之下，在 FXS 中，无法关闭发育性 c 亚基泄漏会阻止依赖于刺激的突触成熟。因此，ATP 合酶 c 亚基泄漏闭合促进发育并减轻自闭症行为。