TRIT1, encoding a tRNA isopentenyl transferase, enables a strong interaction between the mini helix and the codon. It catalyzes the first step in the formation of N6 -isopentenyladenosine (i6 A) or 2 -methylthio -N6 -isopentenyladenosine (ms2 i6 A) modifications at position A37 adjacent to the anticodon in subsets of mitochondrial transfer RNA (tRNA), which is essential for efficient protein translation in mitochondria and energy metabolism [2,3,5,6]. It also has a role in full selenoprotein expression as it is a dimethylallyl:tRNA([Ser]Sec) transferase [4].

Mutations in TRIT1 can lead to a recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels [1]. TRIT1 bi -allelic alterations cause an autosomal recessive disorder, named combined oxidative phosphorylation deficiency 35, with microcephaly, developmental disability, and epilepsy due to decreased mitochondrial function [2]. In patients, a marked decrease in i6 A and ms2 i6 A modifications was observed in RNA nucleoside from peripheral blood and urine, indicating a mitochondrial disorder caused by defective tRNA isopentenylation from TRIT1 loss-of-function mutation [3].

In conclusion, TRIT1 is crucial for tRNA modification, mitochondrial function, and selenoprotein expression. Its dysfunction is associated with severe neurodevelopmental diseases. Understanding TRIT1 through research can provide insights into the mechanisms of these diseases and potentially lead to new diagnostic and therapeutic strategies.