Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis

Area of Science:

• Molecular Biology
• Microbiology
• Gastroenterology

Background:

• Transfer RNA (tRNA) modifications are crucial for translation fidelity and efficiency, regulated by specific enzymes.
• Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) and QTRT 2 form a complex involved in tRNA Queuosine (tRNA-Q) modification.
• Previous research linked tRNA modopathies and altered queuine metabolites to inflammatory bowel diseases (IBD).

Purpose of the Study:

• To investigate the role of tRNA-Q modifications in maintaining intestinal mitochondrial homeostasis and microbiome balance.
• To explore the therapeutic potential of QTRT1 in anti-inflammatory strategies for IBD.

Main Methods:

• Analysis of human IBD datasets and QTRT1 knockout (KO) mouse models.
• Utilized QTRT1 intestinal epithelial conditional KO (QTRT1 ΔIEC) mice, cell lines with QTRT1 siRNA, and patient-derived organoids.
• Examined mucosal barrier integrity, mitochondrial function, microbiome composition, and inflammatory markers.

Main Results:

• Reduced QTRT1 expression observed in human IBD patients and QTRT1 KO mice, correlating with altered gut microbiota (e.g., decreased Bacteroides).
• QTRT1 deficiency led to mucosal barrier damage, impaired tight junctions, and significant mitochondrial dysfunction (decreased ATP synthesis, mtDNA leakage).
• Mitochondrial dysfunction in QTRT1-deficient models triggered cell death and immune activation, mirrored in IBD patient organoids.

Conclusions:

• QTRT1 and its tRNA-Q modification are critical for maintaining intestinal and microbial homeostasis.
• QTRT1 loss disrupts mitochondrial integrity and mucosal barrier function, contributing to IBD pathogenesis.
• Targeting tRNA-Q modification to enhance mitochondrial function presents a novel therapeutic approach for intestinal health.