A formyl axis links metabolism to translation

Initiator methionine tRNA is a key regulator of translation and cell growth. Recent work places formyl chemistry as a regulatory nexus across three molecular layers. In the protein layer, N-formylmethionine supports initiator tRNA recognition and stress-responsive proteostasis pathways. In the RNA layer, 5-formylcytidine at C34 of mitochondrial tRNA^Met expands AUG/AUA decoding. In the DNA layer, 5-formylcytosine activates polymerase III transcription of tRNA_i^Met gene clusters during frog zygotic genome activation. Despite distinct formylation routes and readouts, these layers converge on translational regulation and share metabolic dependencies. One-carbon metabolism supplies methyl/formyl precursors, while mitochondrial and oxidative states influence formyl-mark installation through redox balance and α-ketoglutarate-dependent dioxygenase activity. Together, these layers suggest a formyl-dependent rheostat linking metabolic state to translation capacity.