A selective inhibitor reveals roles for LONP1 in mitochondrial proteostasis and OXPHOS dependencies.

Authors

Zsolt Szilagyi, Pauline Michon, Carlos Pardo-Hernández, Mãdãlina Sãcultanu, Javier Miralles Fusté, Andrew M Griffin, Paul S Charifson, Cindy Phan, Yonghong Shi, Gunther Kern, Gabriel Martinez Botella, Thomas A Keating, Bertil Macao, Nils-Göran Larsson, Maria Falkenberg, Jeremy Green, Claes M Gustafsson

Published in

Life science alliance. Volume 9. Issue 12. Epub Oct 01, 2026.

Abstract

Lon protease 1 (LONP1) is a conserved hexameric protease implicated in mitochondrial disorders and cancer progression. In this study, we present PZL-26, a potent and selective small-molecule inhibitor that targets LONP1 without affecting the proteasome, leading to selective accumulation of mitochondrial proteins. Using PZL-26 in a whole-genome CRISPR-Cas9 screen, we identified genes essential for cell survival under protease inhibition, supporting a role for LONP1 in key mitochondrial processes, including complex I biogenesis, mitochondrial transcription, and translation. Our CRISPR screen results are consistent with proteomics analysis, with both approaches converging on the same mitochondrial pathways and highlighting functional interactions between LONP1 and other mitochondrial proteases, including potential compensatory mechanisms. These findings establish PZL-26 as an effective tool for exploring LONP1 function and pave the way for future therapeutic strategies targeting LONP1 in mitochondrial diseases and cancer.

PMID:
42823380
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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