Mitochondrial LONP1: Linking structure and function to context‑dependent roles in disease (Review)

Mitochondrial proteostasis is essential for maintaining organellar integrity, metabolic adaptation and cellular survival under physiological and stress conditions. Among mitochondrial quality control mechanisms, Lon peptidase 1 (LONP1) is an ATP‑dependent AAA+ serine protease localized predominantly in the mitochondrial matrix and plays a central role in the recognition and degradation of damaged or misfolded proteins. Recent structural, molecular and multi‑omics studies have expanded our understanding of LONP1 beyond proteolysis, implicating it in protein quality control, mitochondrial DNA maintenance, metabolic regulation and responses to oxidative and cellular stress. Increasing evidence also indicates that LONP1 functions are highly dependent on cellular and disease context, with both loss and gain of LONP1 activity associated with distinct pathological outcomes. The present review integrated recent structural and functional advances to establish a structure‑function framework for understanding how LONP1 coordinates proteolytic and chaperone‑like activities and how these functions are shaped by cellular and disease context. The present review further examined its roles in metabolic, neurodegenerative, reproductive, cardiovascular and malignant diseases, with particular emphasis on the context‑dependent consequences of LONP1 dysregulation and its emerging therapeutic potential. Finally, the present review highlighted unresolved questions concerning substrate recognition and specificity, the relative contributions of protease and chaperone‑like functions, disease‑specific directionality and the safety and feasibility of therapeutic modulation. These challenges need to be addressed to establish the functional and translational boundaries of LONP1.