Pnpt1, also known as Polyribonucleotide Nucleotidyltransferase PNPase 1, is a mitochondrial protein that plays critical roles in mitochondrial homeostasis. It controls mitochondrial RNA (mt-RNA) processing, trafficking, and degradation. It is involved in preventing the abnormal accumulation of double-stranded mtRNAs in mitochondria and their leakage into the cytoplasm, thus regulating the type I interferon response [2,4,5,6].

Myeloid-specific Pnpt1-knockout mice demonstrated that Pnpt1 depletion enhanced interleukin-1β (IL-1β) and interleukin-18 (IL-18) secretion in a mouse sepsis model. Pnpt1 deficiency in macrophages increased glycolysis after lipopolysaccharide (LPS) administration and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on increased glycolysis and the expression of mitochondrial antiviral-signaling protein (MAVS) but not NF-κB signaling [1]. Tubular-specific Pnpt1-knockout mice display Fanconi syndrome-like phenotypes with impaired reabsorption and significant renal tubular injury, revealing that Pnpt1 protects renal tubules by blocking the mt-dsRNA-PKR-eIF2α axis [3].

In conclusion, Pnpt1 is essential for maintaining mitochondrial homeostasis and regulating inflammation. Gene-knockout mouse models have revealed its role in sepsis-related inflammation and renal tubular protection. Understanding Pnpt1 function provides insights into the mechanisms of these biological processes and potential disease-associated pathways.