Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant
5 affiliations
- 1Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, Via dell’Istria 65, 34137 Trieste, Italy
- 2Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy
- 3National PhD Program in RNA Therapeutics and Gene Therapy, University of Naples Federico II, 80138 Napoli, Italy
- 4Regional Coordinating Center for Rare Diseases, 33100 Udine, Italy
- 5Neuroradiology Unit, University Hospital, 33100 Udine, Italy
Abstract
Pathogenic variants in MT-RNR1 are classically associated with aminoglycoside-induced sensorineural hearing loss through disruption of the mitochondrial 12S rRNA decoding center. Their contribution to pediatric neurological disease remains poorly defined. We identified a novel homoplasmic MT-RNR1 variant, m.1014A>G, in a patient with drug-resistant focal epilepsy beginning at 9 months of age who remained undiagnosed after trio whole-exome sequencing filtered using an extensive epilepsy gene panel. The variant was also detected in her mother. Structural modeling suggests that the variant, affecting a highly conserved region of the mitochondrial 12S rRNA, may alter the mitochondrial small ribosomal subunit assembly. To investigate its pathogenicity, we performed comprehensive functional studies in patient-derived fibroblasts. Unlike canonical MT-RNR1 variants, m.1014A>G did not confer aminoglycoside toxicity. Functional in vitro studies on patients’ fibroblasts demonstrated increased 12S/16S rRNA ratios, reduced abundance of both mitoribosomal subunit proteins, decreased levels of mitochondrially encoded respiratory-chain subunits, and impaired oxidative phosphorylation. These abnormalities were accompanied by mitochondrial network fragmentation, increased mitochondria–lysosome colocalization suggestive of enhanced mitophagy and reduced mitochondrial DNA copy number. Altogether, the findings are consistent with defective mitoribosome assembly and altered mitochondrial translation, resulting in a bioenergetic defect. Our study points to a previously unrecognized candidate pathogenic mechanism associated with MT-RNR1 and may expand the phenotypic spectrum of MT-RNR1-related disorders to include maternally inherited infantile-onset epileptic encephalopathy. These findings highlight the importance of dedicated mitochondrial DNA analysis in children with unexplained early-onset epilepsy despite negative nuclear genomic testing.
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BibTeX
@article{marrone2026impaired,
title = {{Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant}},
author = {Irene Marrone and Blendi Ura and Fulvio Celsi and Luisa Zupin and Eduardo Maria Sommella and Valentina Golino and Paolo Peruzzo and Chiara Ciardi and Maria Teresa Bonati and Elena Genova and Massimo Zeviani and Alessandro Mauro Spinelli and Valeria Capaci},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219513},
url = {https://www.mdpi.com/1422-0067/27/21/9513},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Impaired Mitochondrial Translation and Bioenergetic Dysfunction Associated with the MT-RNR1 m.1014A>G Variant
AU - Irene Marrone
AU - Blendi Ura
AU - Fulvio Celsi
AU - Luisa Zupin
AU - Eduardo Maria Sommella
AU - Valentina Golino
AU - Paolo Peruzzo
AU - Chiara Ciardi
AU - Maria Teresa Bonati
AU - Elena Genova
AU - Massimo Zeviani
AU - Alessandro Mauro Spinelli
AU - Valeria Capaci
PY - 2026
DA - 2026/10/24
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219513
UR - https://www.mdpi.com/1422-0067/27/21/9513
AB - Pathogenic variants in MT-RNR1 are classically associated with aminoglycoside-induced sensorineural hearing loss through disruption of the mitochondrial 12S rRNA decoding center. Their contribution to pediatric neurological disease remains poorly defined. We identified a novel homoplasmic MT-RNR1 variant, m.1014A>G, in a patient with drug-resistant focal epilepsy beginning at 9 months of age who remained undiagnosed after trio whole-exome sequencing filtered using an extensive epilepsy gene panel. The variant was also detected in her mother. Structural modeling suggests that the variant, affecting a highly conserved region of the mitochondrial 12S rRNA, may alter the mitochondrial small ribosomal subunit assembly. To investigate its pathogenicity, we performed comprehensive functional studies in patient-derived fibroblasts. Unlike canonical MT-RNR1 variants, m.1014A>G did not confer aminoglycoside toxicity. Functional in vitro studies on patients’ fibroblasts demonstrated increased 12S/16S rRNA ratios, reduced abundance of both mitoribosomal subunit proteins, decreased levels of mitochondrially encoded respiratory-chain subunits, and impaired oxidative phosphorylation. These abnormalities were accompanied by mitochondrial network fragmentation, increased mitochondria–lysosome colocalization suggestive of enhanced mitophagy and reduced mitochondrial DNA copy number. Altogether, the findings are consistent with defective mitoribosome assembly and altered mitochondrial translation, resulting in a bioenergetic defect. Our study points to a previously unrecognized candidate pathogenic mechanism associated with MT-RNR1 and may expand the phenotypic spectrum of MT-RNR1-related disorders to include maternally inherited infantile-onset epileptic encephalopathy. These findings highlight the importance of dedicated mitochondrial DNA analysis in children with unexplained early-onset epilepsy despite negative nuclear genomic testing.
SN - 1422-0067
ER -