title: Complex mitochondrial DNA rearrangements in individual cells from patients with sporadic inclusion body myositis.
abstract: Mitochondrial DNA (mtDNA) rearrangements are an important cause of mitochondrial disease and age related mitochondrial dysfunction in tissues including brain and skeletal muscle. It is known that different mtDNA deletions accumulate in single cells, but the detailed nature of these rearrangements is still unknown. To evaluate this we used a complementary set of sensitive assays to explore the mtDNA rearrangements in individual cells from patients with sporadic inclusion body myositis, a late-onset inflammatory myopathy with prominent mitochondrial changes. We identified large-scale mtDNA deletions in individual muscle fibres with 20% of cytochrome c oxidase-deficient myofibres accumulating two or more mtDNA deletions. The majority of deletions removed only the major arc but ∼10% of all deletions extended into the minor arc removing the origin of light strand replication (OL) and a variable number of genes. Some mtDNA molecules contained two deletion sites. Additionally, we found evidence of mitochondrial genome duplications allowing replication and clonal expansion of these complex rearranged molecules. The extended spectrum of mtDNA rearrangements in single cells provides insight into the process of clonal expansion which is fundamental to our understanding of the role of mtDNA mutations in ageing and disease.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK Newcastle University Centre for Ageing and Vitality, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK karolina.rygiel@ncl.ac.uk.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Rygiel
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Tuppen
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Grady
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK Newcastle University Centre for Ageing and Vitality, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK Newcastle University Centre for Ageing and Vitality, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Reeve
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Division of Behavioral Medicine, Department of Psychiatry, Department of Neurology and CTNI, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: Department of Neurology, Newcastle upon Tyne Hospitals NHS Foundation Trust Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK Newcastle University Centre for Ageing and Vitality, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK doug.turnbull@newcastle.ac.uk.
authors.forename: Doug M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001706:Biopsy; D002648:Child; D004272:DNA, Mitochondrial; D005260:Female; D015321:Gene Rearrangement; D054629:Genome, Mitochondrial; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial