LONP1

LonP1, also known as LON protease homolog, is a mitochondrial ATP-dependent serine protease encoded by the LONP1 gene located on chromosome 3. The protein is a component of the mitochondrial matrix and belongs to the AAA+ protease family. LonP1 is essential for mitochondrial protein quality control; it degrades misfolded, oxidatively damaged, or regulatory proteins, thereby maintaining mitochondrial proteostasis and preventing the accumulation of dysfunctional proteins that could compromise respiratory chain activity.

The protein comprises an N‑terminal mitochondrial targeting sequence, a central AAA+ ATPase domain that drives substrate unfolding, and a C‑terminal proteolytic chamber that contains the catalytic serine residue. LonP1 also binds mitochondrial DNA, and recent evidence suggests a role in regulating mtDNA maintenance and transcription. Through these activities, LonP1 supports cellular energy metabolism, regulates reactive oxygen species production, and influences apoptotic signaling.

Loss‑of‑function mutations in LONP1 are associated with severe multisystem disorders such as cranio‑acromelic dysplasia with alopecia, deafness, and short stature (CODAS syndrome). Haploinsufficiency leads to impaired mitochondrial translation and defective respiratory chain assembly, causing neurological and muscular symptoms. Conversely, increased LonP1 expression is observed in various cancers, including breast, prostate, and colorectal tumors, where it promotes cell survival by protecting cancer cells from proteotoxic stress under hypoxic or nutrient‑deprived conditions. Elevated LonP1 levels are also implicated in neurodegenerative diseases, such as Parkinson’s disease, where it may modulate the degradation of aggregated proteins.

Because of its central role in mitochondrial quality control and disease, LonP1 has emerged as a potential therapeutic target. Small‑molecule inhibitors of LonP1’s proteolytic activity have shown cytotoxic effects in cancer cell lines, and genetic knockdown of LonP1 sensitizes cells to oxidative stress. Ongoing research focuses on developing selective modulators that could treat mitochondrial disorders and anticancer therapies by manipulating LonP1 activity.