TRMU encodes a mitochondrial tRNA 2-thiouridylase that catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu), and tRNA(Gln), forming 5-taurinomethyl-2-thiouridine (tm5s2U) 1. This ATP-dependent modification is essential for accurate mitochondrial protein synthesis and translational fidelity 1. TRMU localizes to mitochondria and is ubiquitously expressed but particularly abundant in high-metabolic tissues including heart, liver, brain, and kidney 2. Biallelic TRMU variants cause transient infantile liver failure (ALF) occurring exclusively in the first year of life, with most cases showing remarkable reversibility 3. Of 62 documented patients, 42 survived after median follow-up of 3.6 years, with ALF occurring in 43 individuals; cysteine supplementation (typically N-acetylcysteine) significantly improved survival 3. Loss-of-function variants associate with worse outcomes 3. Additionally, TRMU variants act as nuclear modifiers influencing the phenotypic expression of mitochondrial 12S rRNA A1491G deafness-associated mutations 2. Reduced TRMU expression increases hair cell sensitivity to aminoglycoside-induced ototoxicity through enhanced mitochondrial dysfunction and reactive oxygen species accumulation 4. The therapeutic potential of cysteine supplementation in TRMU deficiency suggests targeting this metabolic pathway offers promise for disease management 5.