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Modulation of Lonp1 Activity by Small Compounds.

Giada Zanini1, Giulia Micheloni1, Giorgia Sinigaglia1

  • 1Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Biomolecules
|April 30, 2025
PubMed
Summary

Lon protease homolog 1 (LONP1) is vital for mitochondrial health. Modulators targeting LONP1 show promise for treating diseases linked to mitochondrial dysfunction and proteostasis imbalance, including cancer and PCOS.

Keywords:
CDDOLon proteaseartemisininbardoxolonebortezomibcancer therapyproteasome inhibitorsprotein quality controlproteostasis

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Area of Science:

  • Mitochondrial Biology
  • Proteostasis
  • Drug Discovery

Background:

  • The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease crucial for cellular homeostasis, proteostasis, and bioenergetics.
  • Dysregulation of LONP1 is linked to pathologies like cancer, metabolic disorders, and reproductive diseases, highlighting its therapeutic potential.

Purpose of the Study:

  • To review compounds that modulate LONP1 activity, categorizing them into inhibitors and activators.
  • To explore the therapeutic implications of LONP1 modulation in various diseases.

Main Methods:

  • Literature review of compounds targeting LONP1.
  • Categorization of modulators into inhibitors (e.g., CDDO, Obtusilactone A, MG262) and activators (e.g., Artemisinin derivatives, 84-B10).

Main Results:

  • LONP1 inhibitors impair mitochondrial proteolysis and promote apoptosis, showing efficacy in cancer models.
  • LONP1 activators restore mitochondrial function and offer protection against conditions like polycystic ovary syndrome (PCOS) and acute kidney injury (AKI).

Conclusions:

  • Compounds modulating LONP1 activity represent a promising therapeutic strategy for diseases associated with mitochondrial dysfunction.
  • Further research is needed to optimize the specificity, bioavailability, and pharmacokinetics of LONP1 modulators for clinical application.