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

Szilagyi Z, Michon P, Pardo-Hernández C, Sãcultanu M, Miralles Fusté J, Griffin AM, Charifson PS, Phan C, Shi Y, Kern G, Martinez Botella G, Keating TA, Macao B, Larsson NG, Falkenberg M, Green J, Gustafsson CM

Life Sci. Alliance 9 (12) - [2026-12-00; online 2026-10-01]

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.

CRISPR Functional Genomics [Service]

PubMed 42823380

DOI 10.26508/lsa.202503535

Crossref 10.26508/lsa.202503535

pmc: PMC13631567
pii: 9/12/e202503535
PDB: 31SY
PDB: 6X1M
PDB: 6X27
PDB: 5LF3
PDB: 6ERQ