Modulation of Lonp1 Activity by Small Compounds

Abstract

The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizing them into inhibitors and activators. Inhibitors such as CDDO and its derivatives selectively target LONP1, impairing mitochondrial proteolysis, inducing protein aggregation, and promoting apoptosis, particularly in cancer cells. Compounds like Obtusilactone A and proteasome inhibitors (e.g., MG262) demonstrate potent cytotoxicity, further expanding the therapeutic landscape. Conversely, LONP1 activators, including Artemisinin derivatives and 84-B10, restore mitochondrial function and protect against conditions such as polycystic ovary syndrome (PCOS) and acute kidney injury (AKI). Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance.

Keywords: CDDO; Lon protease; artemisinin; bardoxolone; bortezomib; cancer therapy; proteasome inhibitors; protein quality control; proteostasis.

Figure 1

Three-dimensional structure of the hexameric LONP1 complex. Chains A, C, E are shown in white, whereas chains B, D, F are in violet; the enzyme is shown complexed with poly-alanine (red), according to 7kms.pdb. ATP and ADP in yellow sticks, whereas Mg are in green spheres.

Figure 2

The 2D structures of 10 inhibitors and 2 activators were generated using the PubChem structure editor. The PubChem IDs are reported under the 2D structures of the indicated ligands. Phenylcoumarin analogs lacking on the PubChem database were derived starting from the indicated PIDs.