PNPT1 encodes polynucleotide phosphorylase (PNPase), a 3'-to-5' exoribonuclease localized to the mitochondrial intermembrane space and matrix 1. Primary functions include catalyzing phosphorolysis of single-stranded polyribonucleotides and serving as a core component of the mitochondrial degradosome (mtEXO) complex, which degrades double-stranded RNA with 3'-to-5' directionality 1. PNPT1 processes non-coding mitochondrial transcripts, facilitates mRNA polyadenylation, and mediates cytoplasmic RNA import into mitochondria 2. Additionally, PNPT1 functions as a cytoplasmic exoribonuclease degrading specific mRNAs and microRNAs, and participates in oxidized RNA surveillance 3. A critical protective mechanism involves PNPT1 restricting accumulation of mitochondrial double-stranded RNA (mt-dsRNA) and preventing its cytoplasmic escape, thereby suppressing MDA5-driven antiviral signaling and preventing inflammatory responses 12. Mutations in PNPT1 cause mt-dsRNA accumulation coupled with interferon upregulation 1. PNPT1 deficiency also triggers the mt-dsRNA-PKR-eIF2α axis, leading to translational arrest and renal tubular atrophy in chr2 kidney disease 4. Clinically, PNPT1 mutations associate with autosomal recessive deafness (DFNB70) presenting with sensorineural hearing loss and vestibular dysfunction 5, and spinocerebellar ataxia 25 6. PNPT1 reduction occurs in metabolic-associated fatty liver disease and hepatocellular carcinoma, suggesting context-dependent roles in disease progression 78.