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

Published in
Cell Metabolism

Abstract
Why mitochondrial function declines with age is a long-standing question. This paper reports an unexpected role for a tRNA-derived fragment generated from tRNA(Glu). This fragment, named tRF-Glu, builds up in multiple tissues as organisms age and damages mitochondria by blocking mitochondrial translation and the organization of cristae. Higher tRF-Glu levels cut glutamate biosynthesis and disturb cellular metabolic balance. Mechanistically, the fragment suppresses mitochondrial proteins needed for respiratory chain performance, causing energy deficits. These observations position tRNA-derived molecules as regulatory factors that couple aging to mitochondrial dysfunction and metabolic decline.

Results

• Aging drives accumulation of a specific tRNA(Glu)-derived fragment (tRF-Glu) across multiple tissues.
• Elevated tRF-Glu impairs mitochondrial translation.
• tRF-Glu disrupts cristae organization and respiratory chain integrity.
• Mitochondrial dysfunction lowers glutamate biosynthesis and reshapes cellular metabolism.
• Restoring mitochondrial function rescues glutamate production.
• Suppressing tRF-Glu improves mitochondrial activity and metabolic homeostasis in aging models.
• The work identifies tRNA-derived fragments as regulators of age-associated metabolic remodeling and mitochondrial health.

trna-charging-analysis-in-aging-mitochondrial-metabolism_1.png

Fig. 1. Aging-induced tRF-Glu disrupts mitochondrial translation and cristae organization, reducing glutamate biosynthesis and driving metabolic dysfunction.

Conclusion
The study shows that tRNA biology reaches beyond protein synthesis to influence aging. An aging-associated tRNA(Glu)-derived fragment acts as a regulatory RNA that damages mitochondrial translation and architecture, resulting in impaired glutamate biosynthesis and metabolic decline. These findings uncover an unrecognized connection between tRNA-derived molecules, mitochondria, and aging, and they highlight tRNA-related pathways as candidate targets for age-associated metabolic disorders.

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