Altered 2-thiouridylation impairs mitochondrial translation in reversible infantile respiratory chain deficiency

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Childhood-onset mitochondrial encephalomyopathies are severe progressive disorders.
• Reversible infantile respiratory chain deficiency (RIRCD) and reversible infantile hepatopathy are exceptions, showing spontaneous recovery.
• These conditions are linked by the modification of mt-tRNA(Glu), involving the TRMU enzyme.

Purpose of the Study:

• To investigate the functional link between TRMU and mt-tRNA(Glu) modification in RIRCD.
• To explore the therapeutic potential of l-cysteine supplementation for RIRCD and TRMU deficiency.

Main Methods:

• Investigated the effect of TRMU down-regulation on mitochondrial translation in vitro.
• Analyzed 2-thiouridylation levels in skeletal muscle of RIRCD patients.
• Assessed the impact of l-cysteine supplementation on respiratory chain enzyme activities in patient-derived cell lines.

Main Results:

• Down-regulation of TRMU in RIRCD impairs 2-thiouridylation and exacerbates mitochondrial translation defects.
• Reduced 2-thiouridylation was observed in skeletal muscle of symptomatic RIRCD patients.
• L-cysteine supplementation rescued respiratory chain enzyme activities in cell lines with RIRCD and TRMU deficiency.

Conclusions:

• L-cysteine is crucial for optimal TRMU function and mt-tRNA modification.
• L-cysteine supplementation represents a potential therapeutic strategy for RIRCD and TRMU deficiency.
• This approach may benefit a broader range of mitochondrial translation disorders.