Lon protease homolog, mitochondrial (LONP1)

Lon protease homolog, mitochondrial (LONP1) is a highly conserved, nuclear-encoded ATP-dependent serine protease located within the mitochondrial matrix. As a member of the AAA+ (ATPases Associated with diverse cellular Activities) superfamily, it plays a critical role in mitochondrial protein quality control by selectively degrading misfolded, unassembled, or oxidatively damaged proteins, such as aconitase and TFAM. Beyond its proteolytic function, LONP1 acts as a molecular chaperone to facilitate the folding and assembly of mitochondrial protein complexes and binds to mitochondrial DNA (mtDNA) to regulate its maintenance and transcription. In the context of disease, LONP1 is frequently overexpressed in various cancers, where it supports cell survival under hypoxic and oxidative stress conditions, making it a promising therapeutic target. Conversely, loss-of-function mutations in LONP1 are the primary cause of CODAS syndrome, a rare multisystem developmental disorder. Small molecule inhibitors, such as the synthetic triterpenoid CDDO and its derivative CDDO-Me (Bardoxolone methyl), have been shown to directly inhibit LONP1, leading to the accumulation of mitochondrial protein aggregates and the induction of apoptosis in cancer cells.

Other names

LONP1LONLONPLonHSPIM1PRSS15hLONCODASSLon peptidase 1, mitochondrialLon protease-like proteinSerine protease 15Mitochondrial ATP-dependent protease Lon

Inhibition of the proteolytic activity or the ATPase activity of LONP1, which prevents the degradation of damaged proteins and leads to the accumulation of mitochondrial protein aggregates, ultimately triggering apoptosis in cancer cells.