LONP1

Lon protease homolog, mitochondrial is a protease, an enzyme that in humans is encoded by the "LONP1" gene.
Structure.
This gene encodes a mitochondrial matrix protein that is the subunit of a barrel-shaped homo-oligomeric protein complex, the Lon protease. Lon protease is a member of ATP-dependent proteases (AAA+ proteases). Mature and catalytically viable human lon protease complex contains a hexameric ring while other formations of complexes have been observed such as the heptameric ring in "Saccharomyces cerevisiae". A single subunit of lon protease contains three domains, N-domain for protein substrate recognition, AAA + module for ATP binding and hydrolysis, and P-domain for protein proteolysis. A similar protease expressed in "E.coli." regulates gene expression by targeting specific regulatory proteins for degradation. Lon protease binds a specific sequence in the light and heavy chain promoters of the mitochondrial genome which are involved in regulation of DNA replication and transcription.
Function.
Lon protease (LONP1) is a conserved serine peptidase identified from bacteria to eukaryotic cells. In mitochondrial matrix, a majority of damaged proteins is removed via proteolysis led by Lon protease, which is an essential mechanism for mitochondrial protein quality control. LONP1 is the major protease responsible for the recognition and removal of unfolded proteins in the mitochondrial matrix and thereby protects the cell from the accumulation of aggregated proteins in the mitochondrion. However LONP1 is unable to recognise or degrade model aggregated proteins.
For Lon protease-dependent degradation, protein substrates are first recognized and then unfolded if necessary in an ATP-dependent manner. The substrates are subsequently transferred through the pore of complex and into the proteolytic chamber of complex for degradation. ATP binding to the AAA module of the Lon complex results in a change in Lon conformation into a proteolytically active state. In general, Lon protease interacts with peptide regions(sequences) that are located within the hydrophobic core of substrates and rarely on the surface. These regions can be presented to Lon protease when proteins are damaged and lost their conformation integrity. In addition to misfolded proteins, several regulatory proteins can be processed by Lon protease by removing a degradable tag before they fully gain their biological functions.
LONP1 is also a DNA-binding protein that participates in mtDNA maintenance and gene expression regulation. LONP1 degrades mitochondrial transcription factor A (TFAM) when substrate is modified by post-translational modifications (PTMs) such as phosphorylation, regulating mtDNA copy number and metabolism to maintain the TFAM/mtDNA ratio necessary to control replication and transcription.
Clinical significance.
Given the crucial role of LON protease in maintaining the control of mitochondrial function, its dynamics in expression under stress conditions has been found associating with human diseases and aging. For example, LONP1 expression levels are increased in different tumors and tumor cell lines. Downregulation of LONP1 in some tumor cells causes apoptosis and cell death, indicating a possible addiction of tumor cells to LONP1 function, as occurs with other intracellular proteases associated with cancer.