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- Table of Contents
Facts about Lon protease homolog, mitochondrial.
Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single- stranded, site-specific, and strand-specific manner.
Human | |
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Gene Name: | LONP1 |
Uniprot: | P36776 |
Entrez: | 9361 |
Belongs to: |
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peptidase S16 family |
EC 3.4.21; EC 3.4.21.-; EC 3.4.21.53; hLON ATP-dependent protease; hLON; lon peptidase 1, mitochondrial; lon protease homolog, mitochondrial; Lon protease-like protein; LON; LonHS; LONP; Mitochondrial ATP-dependent protease Lon; mitochondrial lon peptidase 1; mitochondrial lon protease-like protein; PIM1; protease, serine, 15; PRSS15MGC1498; Serine protease 15
Mass (kDA):
106.489 kDA
Human | |
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Location: | 19p13.3 |
Sequence: | 19; NC_000019.10 (5691834..5720452, complement) |
Duodenum, heart, lung and liver, but not thymus.
Mitochondrion matrix.
Antibodies that detect LONP1 have many benefits. The antibody is specific for the LONP1 gene and can be used in immunotherapy. It has been proven to be a valuable tool in cancer research, especially in melanoma and other types of tumors. We will be exploring the best uses and potential benefits of the LONP1 gene marker in this article.
The LONP1 gene is an important regulator of cellular processes and functions. An increase in the expression of this gene is thought can reduce oxidative, hypoxic or proteotoxic stress levels in cancer cells. LONP1 is thought also to affect mitochondrial energetics (and metabolism), which are both crucial for cancer development. However, further research is required to determine how LonP1 regulates cellular metabolism.
LonP1 contains nearly all-length subunits containing the ATPase & protease domains. The structure of LonP1 can be used for docking studies by identifying the binding pocket CDDO derivatives. Three molecular modeling softwares were used to calculate LonP1's structure. Protein Preparation Wizard was used for optimizing and adding H-atoms to proteins. Further, molecular dynamics simulation was performed using Q-site and restrained minimization techniques.
Furthermore, CDDO derivatives reversed LonP1 activity via a mechanism that was not dependent on peptide bond Hydrolysis. These findings suggest that CDDO derivatives inhibit LonP1 noncompetitively. These results also support the hypothesis that LonP1's pocket overlaps with the ATP/ADP-binding site.
The LONP1 genetic code codes for Lon protease. This is a mitochondrial matrix protein. This protein belongs to ATP-dependent proteases Lon. It is believed to play a role regulating many cellular processes, including the oxidative Stress response, maintenance of mitochondrial DNA and mitophagy. Its presence in cells may also suggest that Lon is a target of SIRT3.
In animal models, intensive research has been conducted on the regulation of LONP1 via CDDO. The role of CDDO is crucial in the regulation of the LONP1 enzyme. CDDO derivatives inhibited LonP1's inhibition of CDDO, with the mutant form showing a greater rate of inhibition that the wild type. Although the mechanism of inhibition is still not fully understood, the study revealed that CDDO derivatives interact via topological properties with the LonP1 Subunit.
LONP1 is part of the AAA+ superfamily ATPases that mediate a variety of cellular processes. In the 26S proteasome, the LonP1 protein is surrounded by two particles: the core particle, which mediates peptide bond hydrolysis, and the regulatory particle, which contains AAA+ family ATPases. In the absence CDDO the 26S proteasesome hydrolyzes ATP.
Lon protease, a mitochondrial enzyme, is one example. It works by selectively degrading rate-limiting proteins or misassembled proteins. Its gene has been conserved throughout evolution, and the mutations of the gene cause CODAS syndrome in humans. Additionally, alterations in LONP1 regulation favor tumor progression and aggressiveness, highlighting the importance of this enzyme in maintaining mitochondrial homeostasis.
LonP1 inhibition is blocked by CDDO-anhydride derivatives CDDO -Me or CDDO -anhydride. These compounds exhibit a high degree selectivity within the AAA+ family of ATPases. CDDO/ADP-binding sites are overlapping in CDDO-Me as well as CDDO/anhydride to inhibit LonP1. However, these compounds can be cytotoxic at high levels.
LonP1 acts as a chaperone and regulates the function mitochondrial functions. Lon's downregulation can cause cell death by impairing mitochondrial structure or function. This gene is associated with a high rate of CDH because it plays an important role during diaphragm formation. Myogenic differentiation requires increased expression of genes involved with mitochondrial biogenesis. Myogenesis can be affected by a mutation in Lonp1.
LONP1 plays a role in tumor cell growth. However, it also regulates the bioenergetics (energy) of cancer cells. This enzyme could be inhibited to treat cancers such as colorectal and melanoma. Although it is not known what the role of LONP1 regulation is in cancer, it is important that we remember that it is necessary for cell viability.
Although it is not clear what LONP1 does, previous studies have shown its essential role in proper functioning of mitochondria. It is believed to perform proteolytic processing of essential protein, which may be crucial for proper cell function. Several pathological conditions, as well as aging, have led to changes in LONP1 gene expression. Although LONP1 plays an important role in cellular health, its function in mammals is not known.
LONP1 increases in expression causes profound changes to mitochondrial complexes. It promotes glycolysis as well as inhibiting mitochondrial respiratory function. LONP1 also regulates OXPHOS-complex structural subunits. These changes may eventually result in the reformation of these complexes. LONP1 regulation in the prevention of cancer is a promising target.
LONP1 regulates a range of other cellular functions, such as mitochondrial ATP synthase. The protease LONP1 protects mitochondria from aggregation. It also helps maintain general stress-dependent protein solubility. These data indicate that LONP1 plays a crucial role in cancer. It is also implicated for maintaining the integrity cell membranes.
Increased tumor formation can be caused by LONP1 upregulation. Cancer cells are less likely to survive and multiply if they have LONP1 blocked. Because both proteins share substrates their depletion affects their ability sustain growth under different conditions. Additionally, the depletion or loss of both genes causes oxidative stress to increase, which ultimately leads cancer cells to die. Finally, both proteins are associated wit a shorter survival time and drug resistance.
CRISPR/Cas was used to generate genetic knockdown of LONP1. The gene was altered by a 7-nt deletion upstream from the start codon, according to analysis of LONP1-knockdown mouse models. Western blot showed a significant drop in LONP1 levels within isolated mitochondria. Quantitative MS characterizations were also performed on LONP1 gKD mitochondrial samples. This revealed a 25% decrease of protease.
Cancer is a complex condition. LONP1 has been implicated with cancer progression. Its suppression reduces tumorigenesis and promotes cellular senescence. Overexpression promotes cancer. LONP1 expression is high in tumor cells and is linked to the Akt pathway. This pathway is responsible enhancing oxidative metabolism. By inhibiting ClpP, you can reduce the number of cancer cells as well as their ability to spread to distant parts of the body.
Lonp1 plays a critical role in cell viability, proliferation, and survival. It also controls bioenergetics. Therefore, inhibition of this protein may be a possible treatment for melanoma as well as colorectal cancer. These findings suggest a possible treatment for colorectal or ovarian cancers, although more research is needed. It's important to note that tumor cells expressed Lonp1 do not have this enzyme in their nuclei.
Metastasis in human melanoma requires LONP1. LONP1 knockdown decreases tumor cells viability in NSCLC- and malignant glioma cell lines. Lonp1 expression increases colony formation, and improves resistance to apoptosis inducing reagents. LonP1 not only plays a role in tumorigenesis but also plays an important part in the progression of cancer.
In human cells, LONP1 expression causes metabolic reprogramming in OXPHOS. LONP1-overexpressing cell decreases the flux of NADH electrons but maintains it through FAD dependent enzymes. These enzymes regulate protein homeostasis within the mitochondrial matrix. The changes in respiration flux that are observed are more closely related with catabolic metabolism than anabolic metabolism.
LONP1 activation causes profound changes in mitochondrial supercomplexes and complexes. It also promotes glycolytic metabolite, which causes inactivation in mitochondrial respiration. LONP1 also regulates tumor metabolic reprogramming. This could be used to treat other malignancies with fast growth that depend on hypoxia for survival. LONP1 inhibiting could be a new treatment option for GBM when used in combination with a chemotherapy or radiation.
Intramitochondrial protein transcription is affected by increased levels of TIM/TOM. Thus, LONP1 gKD cells may have altered levels of intramitochondrial protein translation. They are therefore unable to import mitochondrial encoded proteins. Furthermore, the TIM/TOM system may have been altered in LONP1 gKD cells.
PMID: 8248235 by Wang N., et al. A human mitochondrial ATP-dependent protease that is highly homologous to bacterial Lon protease.
PMID: 20843780 by Wang W., et al. Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing.