近日，美国耶鲁大学Elizabeth A. Jonas、Pawel Licznerski等研究人员合作发现，ATP合酶c亚基泄漏导致脆性X综合征的异常细胞代谢。该项研究成果于2020年8月13日在线发表在《细胞》杂志上。
研究人员发现Fmr1-/y小鼠的神经元具有线粒体内膜泄漏，从而导致“泄漏代谢”。在人类脆性X综合征（FXS）成纤维细胞和Fmr1-/y小鼠神经元中，通过轻度消耗其c亚基或药理学抑制作用来关闭ATP合酶泄漏通道，从而使刺激诱导的和组成型mRNA转化率正常化，降低乳酸盐和关键糖酵解和三羧酸（TCA）循环酶水平，并触发突触成熟。
FMRP（Fragile X mental retardation protein）通过刺激依赖的ATP合酶β亚基翻译来调节野生型（WT）的泄漏关闭，但不调节FX突触的泄漏。这增加了ATP合酶与其c亚基的比率，从而提高了ATP的生产效率和突触生长。相反，在FXS中，无法关闭发育性c亚基泄漏会阻止刺激依赖性突触成熟。因此，ATP合酶c亚基的泄漏关闭能够促进发育并减弱自闭行为。
据悉，编码FMRP的基因（Fmr1）丢失会导致mRNA翻译增加和突触发育异常。
附：英文原文
Title: ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome
Author: Pawel Licznerski, Han-A Park, Harshvardhan Rolyan, Rongmin Chen, Nelli Mnatsakanyan, Paige Miranda, Morven Graham, Jing Wu, Nicole Cruz-Reyes, Nikita Mehta, Sana Sohail, Jorge Salcedo, Erin Song, Charles Effman, Samuel Effman, Lucas Brandao, Gulan N. Xu, Amber Braker, Valentin K. Gribkoff, Richard J. Levy, Elizabeth A. Jonas
Issue&Volume: 2020-08-13
Abstract: Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translationand 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 itsc-subunit or pharmacological inhibition normalizes stimulus-induced and constitutivemRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid(TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closurein wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunittranslation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancingATP production efficiency and synaptic growth. In contrast, in FXS, inability to closedevelopmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore,ATP synthase c-subunit leak closure encourages development and attenuates autisticbehaviors.
DOI: 10.1016/j.cell.2020.07.008
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30873-4