SLIRP differentially modulates RNA binding of pathogenic LRPPRC variants
Year: 2026
Type: article
Abstract: The LRPPRC/SLIRP complex is a key post-transcriptional regulator of mitochondrial gene expression, stabilizing mitochondrial mRNAs and promoting their polyadenylation and translation. Mutations in LRPPRC cause mitochondrial disorders, including Leigh syndrome French-Canadian type (LSFC), primarily affecting oxidative phosphorylation. Here, we examined the RNA-binding properties of wild-type LRPPRC and three pathogenic variants (A354V, K909del, and R1276_K1300del) using electrophoretic mobility shift assays, acoustic force spectroscopy, and AlphaFold 3 modeling. All three mutations reduced intrinsic RNA binding, with R1276_K1300del showing no detectable interaction in the absence of SLIRP. Remarkably, SLIRP restored RNA binding of this mutant to near wild-type levels, likely through conformational stabilization, as supported by single-molecule and structural analyses. These findings highlight SLIRP's critical role in modulating LRPPRC function and suggest that enhancing SLIRP activity represents a potential therapeutic strategy for LRPPRC-related mitochondrial disorders.
Source: NAR Molecular Medicine
Institutions: Centre National de la Recherche Scientifique, Université Clermont Auvergne, Laboratoire de Physique de Clermont Auvergne, University of Gothenburg, Observatoire de Physique du Globe de Clermont-Ferrand, Laboratoire Magmas et Volcans, Institut de Recherche pour le Développement, North China University of Science and Technology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,300
OpenAlex ID: W7204144792