Small molecules rescue pathogenic POLG aggregation and restore its functions in a mouse model of PEO

ABSTRACT: POLG, the catalytic subunit of mitochondrial DNA polymerase, is essential for mitochondrial DNA (mtDNA) replication and maintenance. Mutations in POLG cause progressive external ophthalmoplegia (PEO), but the underlying pathogenic mechanisms remain unclear. We show that the mitochondrial E3 ligase MITOL hyperubiquitylates PEO-associated POLG mutants at lysine 1060, triggering conformational changes and formation of insoluble aggregates that impair their mitochondrial import and consequently compromise mtDNA replication and mitochondrial homeostasis. To identify compounds that disrupt aggregates and restore mutant POLG function, we screened an FDA/EMA/PMDA-approved drug library using a split-GFP assay for POLG aggregation. We identified two clinically approved compounds, diltiazem hydrochlo

SUBMITTER: Aftab Mohammed 

PROVIDER: S-SCDT-10_1038-S44321-026-00532-3 | biostudies-other |

REPOSITORIES: biostudies-other