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

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

doi:10.1016/j.cmet.2024.02.011

Aging-induced tRNA^Glu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization

Cell Metab. 2024 Mar 1:S1550-4131(24)00057-3. doi: 10.1016/j.cmet.2024.02.011. Online ahead of print.

Authors

Dingfeng Li¹, Xinyi Gao¹, Xiaolin Ma¹, Ming Wang², Chuandong Cheng³, Tian Xue², Feng Gao⁴, Yong Shen⁵, Juan Zhang⁶, Qiang Liu⁷

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230001, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Diseases, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
² Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Diseases, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
³ Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
⁴ Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230001, China.
⁵ Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230001, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Diseases, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disorder Research Center, Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei 230026, China.
⁶ Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230001, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Diseases, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: zj2014@ustc.edu.cn.
⁷ Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230001, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; CAS Key Laboratory of Brain Function and Diseases, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Neurodegenerative Disorder Research Center, Anhui Province Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei 230026, China; Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, Hefei 230001, China. Electronic address: liuq2012@ustc.edu.cn.

PMID: 38458203
DOI: 10.1016/j.cmet.2024.02.011

Abstract

Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging are largely elusive. Here, we observe an age-dependent accumulation of Glu-5'tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNA^Glu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNA^Leu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNA^Leu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translation defects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels. Moreover, reduction of Glu-5'tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory. Thus, beyond illustrating a physiological role for normal mitochondrial cristae ultrastructure in maintaining glutamate levels, our study defines a pathological role for tsRNAs in brain aging and age-related memory decline.

Keywords: angiogenin; brain aging; cristae organization; glutamate metabolism; memory decline; mitochondria; mitochondrial translation; tRNA-derived small RNAs.