Summary: A new study identifies a crucial factor in brain aging and Alzheimer’s disease—the accumulation of Glu-5’tsRNA-CTC in neuron mitochondria. This small RNA fragment disrupts mitochondrial protein synthesis and cristae structure, accelerating cognitive decline and Alzheimer’s pathology.
By targeting these tRNA fragments with antisense oligonucleotides in aged mice, the researchers successfully reversed memory deficits, suggesting a potential new treatment strategy. This study highlights the significant role mitochondrial dysfunction plays in neurodegenerative diseases and opens avenues for therapeutic interventions.
Key Facts:
- Glu-5’tsRNA-CTC accumulation in mitochondria impairs critical components of cellular energy production, hastening brain aging and Alzheimer’s disease.
- Targeted intervention with antisense oligonucleotides in mice has been shown to alleviate learning and memory impairments associated with aging.
- The study underscores the importance of maintaining mitochondrial function to prevent cognitive decline, providing new insights into the mechanisms of Alzheimer’s disease.
Source: University of Science and Technology of China
A significant research paper published in the journal Cell Metabolism by the team of Prof. LIU Qiang at the University of Science and Technology of China (USTC) reveals the critical role of glutamate tRNA fragments in brain aging and Alzheimer’s disease.
The study found age-dependent accumulation of Glu-5’tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNAGlu in the mitochondria of glutaminergic neurons.
This abnormal accumulation impairs mitochondrial protein translation and cristae structure, ultimately accelerating the pathological processes of brain aging and Alzheimer’s disease.
Brain aging is an inevitable natural process that leads to a decline in cognitive function. Alzheimer, a neurodegenerative disease, is the most common cause of dementia in the elderly where cognitive impairment is a hallmark feature of Alzheimer’s disease.
Mitochondria, known as the “powerhouses” of cells, provide energy to cells. Research has shown that mitochondrial dysfunction is closely associated with brain aging and Alzheimer’s disease.
Mitochondrial Glu-5’tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase 2 (LARS2), impairing mt-tRNALeu aminoacylation and mitochondrial-encoded protein translation.
Defects in mitochondrial translation disrupt cristae architecture, resulting in impaired glutamine formation dependent on glutaminase (GLS) and reduced synaptic glutamate levels.
Additionally, reducing Glu-5’tsRNA-CTC can protect the aging brain from age-related defects in mitochondrial cristae, glutamine metabolism, synaptic structure, and memory.
LIU and his team shed light on the crucial role of glutamate tRNA fragments in brain aging and Alzheimer’s disease, offering new insights for delaying cognitive decline.
The researchers designed antisense oligonucleotides targeting these tRNA fragments and injected them into the brains of aged mice. This intervention significantly alleviated learning and memory deficits in the aged mice.
In addition to elucidating the physiological role of normal mitochondrial cristae ultrastructure in maintaining glutamate levels, this study also defined the pathological role of transfer RNAs in brain aging and age-related memory decline.
About this Alzheimer’s disease research news
Author: Jane Fan
Source: University of Science and Technology of China
Contact: Jane Fan – University of Science and Technology of China
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization” by Dingfeng Li et al. Cell Metabolism
Abstract
Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization
Highlights
- Aging induces cytoplasmic localization of angiogenin to produce Glu-5′tsRNA-CTC
- Glu-5′tsRNA-CTC disrupts mitochondrial translation and cristae organization
- Cristae ultrastructure is required to maintain glutamate homeostasis in the brain
- ASO targeting Glu-5′tsRNA-CTC rescues memory decline in aged mice
Summary
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 tRNAGlu in the mitochondria of glutaminergic neurons.
Mitochondrial Glu-5′tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNALeu 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.
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