The presence of highly disruptive 16S rRNA mutations in clinical samples indicates a wider role for mutations of the mitochondrial ribosome in human disease.
Mitochondrial DNA mutations are well recognized as an important cause of disease, with over two hundred variants in the protein encoding and mt-tRNA genes associated with human disorders. In contrast, the two genes encoding the mitochondrial rRNAs (mt-rRNAs) have been studied in far less detail. This is because establishing the pathogenicity of mt-rRNA mutations is a major diagnostic challenge. Only two disease causing mutations have been identified at these loci, both mapping to the small subunit (SSU). On the large subunit (LSU), however, the evidence for the presence of pathogenic LSU mt-rRNA changes is particularly sparse. We have previously expanded the list of deleterious SSU mt-rRNA mutations by identifying highly disruptive base changes capable of blocking the activity of the mitoribosomal SSU. To do this, we used a new methodology named heterologous inferential analysis (HIA). The recent arrival of near-atomic-resolution structures of the human mitoribosomal LSU, has enhanced the power of our approach by permitting the analysis of the corresponding sites of mutation within their natural structural context. Here, we have used these tools to determine whether LSU mt-rRNA mutations found in the context of human disease and/or ageing could disrupt the function of the mitoribosomal LSU. Our results clearly show that, much like the for SSU mt-rRNA, LSU mt-rRNAs mutations capable of compromising the function of the mitoribosomal LSU are indeed present in clinical samples. Thus, our work constitutes an important contribution to an emerging view of the mitoribosome as an important element in human health.
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom; Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa.
Joanna L
JL
Elson
Institute of Medical Sciences, Ninewells Hospital and Medical School, Dundee University, Dundee DD1 9SY, Scotland, UK; Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom.
Paul M
PM
Smith
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom.
Laura C
LC
Greaves
Newcastle University Institute for Cell and Molecular Biosciences, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom.
Robert N
RN
Lightowlers
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom.
Zofia M A
ZM
Chrzanowska-Lightowlers
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom.
Robert W
RW
Taylor
Grupo GIBE, Bioloxía Celular e Molecular, Facultade de Ciencias, Universidade da Coruña (UDC), Campus Zapateira s/n, 15071 A Coruña, Spain. Electronic address: antonvila.s@gmail.com.
Antón
A
Vila-Sanjurjo
D019295:Computational Biology; D004272:DNA, Mitochondrial / Q000235:genetics; D004275:DNA, Ribosomal / Q000737:chemistry / Q000235:genetics; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D000069396:Mitochondrial Ribosomes; D008958:Models, Molecular; D009154:Mutation; D009690:Nucleic Acid Conformation; D012336:RNA, Ribosomal, 16S / Q000235:genetics*; D012338:RNA, Ribosomal, 23S / Q000235:genetics*
D004272:DNA, Mitochondrial; D004275:DNA, Ribosomal; D012336:RNA, Ribosomal, 16S; D012338:RNA, Ribosomal, 23S
Mitochondrial disease; Mitochondrial rRNA; Mitoribosome; MtDNA; rRNA mutation