中国科学技术大学刘强等研究人员合作发现，衰老引起的tRNA^Glu衍生片段通过靶向线粒体翻译依赖性嵴组织来损害谷氨酸的生物合成。2024年3月7日，《细胞—代谢》杂志在线发表了这项成果。

研究人员观察到谷氨酸能神经元线粒体中Glu-5′tsRNA-CTC（一种转运RNA衍生的小RNA（tsRNA））的积累与年龄有关，这种小RNA来自核编码的tRNA^Glu。线粒体 Glu-5′tsRNA-CTC 破坏了mt-tRNA^Leu和亮氨酰-tRNA 合成酶2（LaRs2）的结合，损害了mt-tRNA^Leu氨基酰化和线粒体编码的蛋白质翻译。线粒体翻译缺陷破坏了嵴的组织，导致谷氨酰胺酶（GLS）依赖性谷氨酸形成受损和突触体谷氨酸水平降低。

此外，Glu-5′tsRNA-CTC的减少能保护老年大脑免受线粒体嵴组织、谷氨酸代谢、突触结构和记忆中与年龄相关的缺陷的影响。因此，除了说明正常线粒体嵴超微结构在维持谷氨酸水平中的生理作用外，这项研究还确定了tsRNA在大脑衰老和与年龄相关的记忆衰退中的病理作用。

据悉，线粒体嵴是线粒体内膜的折叠部分，随着年龄的增长，其结构会发生异常变化。然而，其潜在的分子机制及其对大脑衰老的贡献在很大程度上还难以捉摸。

附：英文原文

Title: Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization

Author: Dingfeng Li, Xinyi Gao, Xiaolin Ma, Ming Wang, Chuandong Cheng, Tian Xue, Feng Gao, Yong Shen, Juan Zhang, Qiang Liu

Issue&Volume: 2024-03-07

Abstract: Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrantchanges in their architecture with age. However, the underlying molecular mechanismsand their contribution to brain aging are largely elusive. Here, we observe an age-dependentaccumulation of Glu-5′tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derivedfrom nuclear-encoded tRNAGlu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5′tsRNA-CTC disruptsthe binding of mt-tRNALeu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNALeu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translationdefects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependentglutamate formation and reduced synaptosomal glutamate levels. Moreover, reductionof Glu-5′tsRNA-CTC protects aged brains from age-related defects in mitochondrialcristae organization, glutamate metabolism, synaptic structures, and memory. Thus,beyond illustrating a physiological role for normal mitochondrial cristae ultrastructurein maintaining glutamate levels, our study defines a pathological role for tsRNAsin brain aging and age-related memory decline.

DOI: 10.1016/j.cmet.2024.02.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00057-3