Lon protease homolog 1, mitochondrial (LONP1)

Lon protease homolog 1, mitochondrial (LONP1) is a nuclear-encoded AAA+ serine protease that resides within the mitochondrial matrix and serves as a primary component of the mitochondrial protein quality control system (UniProt P36776). It is responsible for the degradation of misfolded, damaged, or oxidized proteins and also functions as a molecular chaperone and a regulator of mitochondrial DNA (mtDNA) maintenance (PubMed: 26045068). LONP1 is frequently upregulated in various malignancies, including colorectal and lung cancers, where it facilitates metabolic adaptation and protects cells from oxidative stress-induced apoptosis (PubMed: 30107129). Consequently, LONP1 is considered a promising therapeutic target in oncology, with small molecules like bardoxolone methyl (CDDO-Me) demonstrating inhibitory activity against its proteolytic function (PubMed: 24603304). However, the essential nature of LONP1 is underscored by the fact that biallelic mutations in the gene cause CODAS syndrome, a multi-system developmental disorder, suggesting that therapeutic targeting must carefully balance efficacy with potential mitochondrial toxicity (PubMed: 25601445).

Other names

Lon protease 1Mitochondrial Lon proteasehLonLONPLONSerine protease 15PRSS15

Inhibition of the proteolytic activity of LONP1 leads to the accumulation of misfolded and oxidized proteins within the mitochondrial matrix, triggering mitochondrial stress, loss of membrane potential, and induction of apoptosis in cancer cells.