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

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Posttranscriptional nucleotide modifications of transfer RNAs (tRNAs) are crucial for their structure and function.
• Mutations in the TRMU gene lead to deficient modifications (τm⁵s²U) in mitochondrial tRNAs (mt-tRNAs), primarily causing liver failure.
• The mechanisms underlying tissue-specific pathologies in TRMU-deficient conditions remain poorly understood.

Purpose of the Study:

• To investigate the tissue-specific consequences of TRMU deficiency and the loss of τm⁵s²U modifications in mitochondrial tRNAs.
• To elucidate the molecular mechanisms contributing to liver-specific pathogenesis in zebrafish models of TRMU deficiency.

Main Methods:

• Utilized zebrafish as a model organism to study TRMU deficiency.
• Generated trmu knockout (KO) zebrafish to assess tissue-specific effects on tRNA conformation, stability, and aminoacylation.
• Analyzed mitochondrial respiratory chain complex assembly, stability, and activity, focusing on complexes I, III, and IV.

Main Results:

• Observed varying levels of τm⁵s²U modifications in mt-tRNAs (tRNA^Glu, tRNA^Gln, tRNA^Lys) across different zebrafish tissues (brain, muscle, eye, liver, ovum).
• Demonstrated significant tissue-specific alterations in the conformation, stability, and aminoacylation of these mt-tRNAs in trmu^KO zebrafish, with the liver exhibiting the most severe defects.
• Found that aberrant mt-tRNA metabolism in trmu^KO zebrafish disrupted mitochondrial respiratory complexes (I, III, IV), particularly in the liver, leading to altered complex I to complex II ratios and subsequent liver pathologies like steatosis and enlargement.

Conclusions:

• Loss of τm⁵s²U modification in mitochondrial tRNAs due to TRMU deficiency results in tissue-specific defects, contributing to liver pathogenesis.
• The liver's unique metabolic profile, including high reliance on Complex I, makes it particularly vulnerable to disruptions in mitochondrial tRNA function.
• These findings offer novel insights into the molecular basis of liver-specific diseases stemming from impaired mitochondrial tRNA modifications.