Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential

Mitochondria, the primary energy producers in eukaryotic cells, depend on an intricate protein quality control (PQC) system to preserve their functional integrity. Lon protease 1 (LONP1), an adenosine triphosphate (ATP)-dependent serine protease localized in the mitochondrial matrix, maintains mitochondrial proteostasis through selective degradation of misfolded and oxidatively modified proteins. Beyond its proteolytic activity, LONP1 not only acts as a molecular chaperone facilitating protein folding but also directly binds to mitochondrial DNA (mtDNA), suggesting a multifunctional role in mitochondrial genome regulation. LONP1 is tightly regulated through multilayered mechanisms spanning transcriptional control, epigenetic modulation, and post-translational modifications. Emerging evidence establishes mechanistic links between LONP1 and the pathogenesis of various human diseases. In this review, we comprehensively summarize the structural features and multifunctional roles of LONP1, with particular emphasis on its disease-associated molecular mechanisms. We further evaluate existing pharmacological modulators of LONP1 activity, providing a theoretical basis for the development of new therapeutic strategies for related diseases.