Methylation is essential not only for RNA stability — we show it’s structurally required for forming the peptidyl transferase center (PTC). Without it, the mitoribosome stalls at an immature stage, unable to build its catalytic core.

By depleting mitochondria of S-adenosylmethionine (SAM), we disrupt canonical rRNA processing at the ribosomal junctions in MEFs and skeletal muscle. This leads to accumulation of unprocessed transcripts and defective ribosome assembly.

We argued that since mtDNA mutation accumulation is progressive, cellular mechanisms must influence its pathogenicity. Through a genetic screen in fruit flies, we identified pathways that can rescue a lethal mtDNA mutator phenotype. We are excited to test this in higher species.