# Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure

## TL;DR

This study shows how mutations in TRMU cause liver failure by disrupting mitochondrial tRNA modifications, leading to specific metabolic issues in zebrafish livers.

## Contribution

The study reveals the tissue-specific mechanism of liver failure caused by TRMU mutations through mitochondrial tRNA modification deficiencies.

## Key findings

- TRMU deficiency leads to reduced τm5s2U modifications in mitochondrial tRNAs, causing liver-specific metabolic failures.
- Liver tissues show more severe tRNA instability and aminoacylation defects compared to other tissues in trmu KO zebrafish.
- Liver-specific electron flow preferences through complex I contribute to hepatic steatosis and enlargement in trmuKO zebrafish.

## Abstract

Posttranscriptional nucleotide modifications of tRNAs play the critical roles in their structure and function. Deficient τm5s2U modifications of mitochondrial tRNAGlu, tRNAGln and tRNALys arising from TRMU mutations primarily manifest the liver failure. However, mechanisms of tissue specificity in TRMU-induced deficiencies remain largely elusive. In this report, we demonstrated that the loss of τm5s2U in mitochondrial tRNAs due to TRMU-deficiency caused the tissue-specific manifestation that contributed to pathogenesis of liver failures in the zebrafish. A wide range level of τm5s2U in tRNALys, tRNAGlu, and tRNAGln occurred across the zebrafish brain, muscle, eye, liver and ovum tissues. Striking differences in tissue-specific effects of conformation, stability and aminoacylation of tRNAGlu, tRNALys and tRNAGln were observed among five tissues of trmu KO zebrafish. Notably, livers are vulnerable to the loss of τm5s2U of tRNAs, evidenced by more severe failures in these tRNA metabolisms including conformation, instability and aminoacylation in liver than those in other four tissues of trmuKO zebrafish. These aberrant tRNA metabolisms altered the assembly, stability, and activities of complexes I, III and IV, especially pronounced in the liver of trmuKO zebrafish. Notably, livers displayed the highest ratios in the levels and activities of complex I to complex II in across five tissues, indicating the liver-specific electron flow preferences through complex I to coenzyme Q to complex III. These tissue-specific complex I deficiencies manifested the liver failures including hepatic steatosis and enlargement. Our findings provide new insights into the mechanism of liver-specific defects arising from the aberrant nucleotide modification of mitochondrial tRNAs.