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The role of the mitochondrial ribosome in human disease: Searching for mutations in 12S mitochondrial rRNA with high disruptive potential

Lookup NU author(s): Dr Paul Smith, Dr Joanna Elson, Dr Laura Greaves, Professor Robert Lightowlers, Professor Zofia Chrzanowska-LightowlersORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Mutations of mitochondrial DNA are linked to many human diseases. Despite the identification of a large number of variants in the mitochondrially-encoded rRNA (mt-rRNA) genes, the evidence supporting their pathogenicity is, at best, circumstantial. Establishing the pathogenicity of these variations is of major diagnostic importance. Here, we aim to estimate the disruptive effect of mt-rRNA variations on the function of the mitochondrial ribosome. In the absence of direct biochemical methods to study the effect of mt-rRNA variations, we relied on the universal conservation of the rRNA fold to infer their disruptive potential. Our method, named Heterologous Inferential Analysis or HIA, combines conservational information with functional and structural data obtained from heterologous ribosomal sources. Thus, HIA's predictive power is superior to the traditional reliance on simple conservation indexes. By using HIA we have been able to evaluate the disruptive potential for a subset of uncharacterized 12S mt-rRNA variations. Our analysis revealed the existence of variations in the rRNA component of the human mitoribosome with different degrees of disruptive power. In cases where sufficient information regarding the genetic and pathological manifestation of the mitochondrial phenotype is available, HIA data can be used to predict the pathogenicity of mt-rRNA mutations. In other cases, HIA analysis will allow the prioritisation of variants for additional investigation. Eventually, HIA-inspired analysis of potentially pathogenic mt-rRNA variations, in the context of a scoring system specifically designed for these variants, could lead to a powerful diagnostic tool.

Publication metadata

Author(s): Smith PM, Elson JL, Greaves LC, Wortmann SB, Rodenburg RJT, Lightowlers RN, Chrzanowska-Lightowlers ZMA, Taylor RW, Vila-Sanjurjo A

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2013

Volume: 23

Issue: 4

Pages: 949-969

Print publication date: 14/02/2014

Online publication date: 02/10/2013

Acceptance date: 26/09/2013

Date deposited: 06/07/2015

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddt490

Notes: Joint first authors.


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Funder referenceFunder name
Academic fellowship from the Research Council UK
Newcastle University Centre for Brain Ageing and Vitality
096919/Z/11/ZWellcome Trust
AGL2012-39274-C02-02Spanish Ministerio de Economia y Competitividad
G0700718MRC of the cross council Lifelong Health and Wellbeing Initiative
PIIF-GA-2010-274660Marie Curie Actions programme of the European Commission