PDE12 mediated pruning of the poly-A tail of mitochondrial DNA-encoded tRNAs is essential for survival

Mitochondrial DNA (mtDNA)-encoded RNA molecules undergo extensive processing to generate mature RNA, including removal of spurious poly-A tails by phosphodiesterase12 (PDE12). A new study by Van Haute and colleagues (Van Haute et al, 2024) describes the first pathogenic variants in the human PDE12 gene. The 3 missense mutations that were identified each carry severe phenotypic consequences that correlate with the presence or not of residual PDE12 protein, show cell-type-specific adaptive responses, and specificity in the mtDNA-encoded electron transport chain subunits that are most affected. These new data demonstrate the necessity of PDE12 for life, and provide invaluable insights into RNA processing in mitochondria. E Seifert, M Tigano, and C Yu discuss the study from Haute et al, published in this issue of EMBO Mol Med, that reports the first pathogenic variants in the human PDE12 gene causing neonatal mitochondrial disease.