ArticleThe Journal of biological chemistry2022
Inhibition of mitochondrial LonP1 protease by allosteric blockade of ATP binding and hydrolysis via CDDO and its derivatives.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 25 citations in OpenAlex.
- Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.The Journal of clinical investigation · 2026Article
- Mitochondrial stress response drives microglial senescence.Nature neuroscience · 2026Article
- The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.Nature neuroscience · 2026Article
- Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.Antioxidants (Basel, Switzerland) · 2026Review
- Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.bioRxiv : the preprint server for biology · 2026Article
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential.Cellular & molecular biology letters · 2026Review
- Inhibition of LONP1 in prostate cancer: bibliometrics-guided target screening and AI-driven antibody design.International journal of surgery (London, England) · 2026Article
- Proteasomal inhibition compromises microvascular integrity via distinct effects on non-immune endothelial cells and immune cells.Frontiers in immunology · 2026Article
- The role of mitochondrial proteases in inflammation and immunity.Frontiers in immunology · 2026Review
- Lon peptidase 1 promotes proliferation and metastasis in breast cancer via interleukin 6 signaling.Discover oncology · 2025Article
- Identifying a novel Mecp2-mediated epigenetic mechanism controlling Lonp1 in the hippocampus and its disruption by aging.Scientific reports · 2025Article
- Cryo-EM Reveals Regulatory Mechanisms Governing Substrate Selection and Activation of Human LONP1.bioRxiv : the preprint server for biology · 2025Article
- LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.Nature metabolism · 2025Article
- Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.Autophagy · 2025Article
- Dual targeting of the mitochondrial Lon peptidase 1 and the chymotrypsin-like proteasome activity as a potential therapeutic strategy in malignant astrocytoma models.Pharmacological research · 2025Article
- The mitochondrial LONP1 protease: molecular targets and role in pathophysiology.Molecular biology reports · 2025Review
- Modulation of Lonp1 Activity by Small Compounds.Biomolecules · 2025Review
- Cancer Drug Bortezomib, a Proteasomal Inhibitor, Triggers Cytotoxicity in Microvascular Endothelial Cells via Multi-Organelle Stress.bioRxiv : the preprint server for biology · 2025Article
- Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.Cell death & disease · 2025Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The mitochondrial protein LonP1 is an ATP-dependent protease that mitigates cell stress and calibrates mitochondrial metabolism and energetics. Biallelic mutations in the LONP1 gene are known to cause a broad spectrum of diseases, and LonP1 dysregulation is also implicated in cancer and age-related disorders. Despite the importance of LonP1 in health and disease, specific inhibitors of this protease are unknown. Here, we demonstrate that 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its -methyl and -imidazole derivatives reversibly inhibit LonP1 by a noncompetitive mechanism, blocking ATP-hydrolysis and thus proteolysis. By contrast, we found that CDDO-anhydride inhibits the LonP1 ATPase competitively. Docking of CDDO derivatives in the cryo-EM structure of LonP1 shows these compounds bind a hydrophobic pocket adjacent to the ATP-binding site. The binding site of CDDO derivatives was validated by amino acid substitutions that increased LonP1 inhibition and also by a pathogenic mutation that causes cerebral, ocular, dental, auricular and skeletal (CODAS) syndrome, which ablated inhibition. CDDO failed to inhibit the ATPase activity of the purified 26S proteasome, which like LonP1 belongs to the AAA
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.