LONP1 is an ATP-dependent mitochondrial serine protease that maintains mitochondrial proteostasis by selectively degrading misfolded, unassembled, or oxidatively damaged polypeptides, including substrates such as StAR protein, DELE1, Twinkle helicase, and MRPL32 123. The protease regulates mitochondrial gene expression and genome integrity through site-specific, single-stranded DNA binding at mitochondrial promoters, controlling transcription and replication 4. LONP1 selectively degrades specific mitochondrial proteins including HMGCS2 in kidney disease 5, DHODH in liver fibrosis 6, and CYP11A1 in reproductive disorders 7. Dysregulation of LONP1 contributes to multiple pathologies. Decreased LONP1 expression exacerbates chr19 kidney disease by allowing HMGCS2 accumulation and mitochondrial dysfunction 5, while reduced LONP1 in muscle disuse causes impaired mitochondrial protein quality control, leading to muscle atrophy and weakness 8. Rare and de novo variants in LONP1 associate with congenital diaphragmatic hernia, where lung-specific Lonp1 deletion impairs lung development 9. LONP1 also interacts with glucocerebrosidase to maintain mitochondrial complex I integrity 10. Pharmacological LONP1 activation shows therapeutic promise in treating polycystic ovary syndrome, kidney injury, and liver fibrosis 711.