RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo

Abstract Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1 N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1 N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1 N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1 N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.

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Journal
EMBO Molecular Medicine
Published
2026-10-14
DOI
https://doi.org/10.1038/s44321-026-00534-1
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
0.00

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article

RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo

Maria J. Sanchez‐Quintero, May Theng Ting, Agustín Hidalgo‐Gutiérrez, Michal A. Minczuk et al.
EMBO Molecular Medicine
Mitochondrial Function and Pathology
article

RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo

Maria J. Sanchez‐Quintero, May Theng Ting, Agustín Hidalgo‐Gutiérrez, Michal A. Minczuk, Eliana Barriocanal‐Casado, Catarina Maria Quinzii, Kurenai Tanji, Robert McFarland, Antoni Barrientos, Carlos Lopez‐Gómez, Giulio Kleiner, Joanna Rorbach, Eva Nývltová, Robert William Taylor, Christopher B. Damoci, Alba Pesini, Lucia Dec-Prat, Christian Garcia
article en

Abstract

Abstract Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1 N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1 N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1 N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1 N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.

EMBO Molecular Medicine
University of Miami (US), University of Cambridge (GB), Columbia University Irving Medical Center (US), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Bruce W. Carter VA Medical Center (US), Hospital Clínico Universitario Virgen de la Victoria (ES), Instituto de Investigación Biomédica de Málaga (ES), MRC Mitochondrial Biology Unit (GB), Newcastle University (GB)
Muscular Dystrophy Association, Fundación Alfonso Martín Escudero, Muscular Dystrophy UK, LifeArc, National Institute for Health and Care Research, European Commission, Lily Foundation, National Institutes of Health, Irving Medical Center, Columbia University, HORIZON EUROPE Framework Programme, Medical Research Council, National Cancer Institute, National Center for Advancing Translational Sciences
Good health and well-being
Openalex Percentile: Top 24%
Mitochondrial Function and Pathology
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