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Nucleic Acids Res. 2016 Jun 20;44(11):5313-29. doi: 10.1093/nar/gkw382. Epub 2016 Apr 30.

Complex mitochondrial DNA rearrangements in individual cells from patients with sporadic inclusion body myositis.

Author information

1
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.
2
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
3
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.
4
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.
5
Department of Neurology, Newcastle upon Tyne Hospitals NHS Foundation Trust Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
6
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.

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.

PMID:
27131788
PMCID:
PMC4914118
DOI:
10.1093/nar/gkw382
[Indexed for MEDLINE]
Free PMC Article

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