Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia

Ar, Moslemi; Melberg, Atle; Holme, Elisabeth; Oldfors, Anders

doi:10.1002/ana.410400506

Cited by 86 publications

(46 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, focal accumulation of very high levels of individual mtDNA point mutations is likely to be pathogenic in individual cells or segments of skeletal muscle cells. In fact, focal accumulation of pathogenic mtDNA deletions has been identified in COXdeficient skeletal muscle of patients with autosomal dominant progressive external ophthalmoplegia (37) and inclusion body myopathy (38).…”

mentioning

confidence: 99%

Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

Nishigaki¹,

Martí²,

Copeland³

et al. 2003

J. Clin. Invest.

View full text Add to dashboard Cite

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). This deficiency of TP leads to increased circulating levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) and has been associated with multiple deletions and depletion of mitochondrial DNA (mtDNA). Here we describe 36 point mutations in mtDNA of tissues and cultured cells from MNGIE patients. Thirty-one mtDNA point mutations (86%) were T-to-C transitions, and of these, 25 were preceded by 5′-AA sequences. In addition, we identified a single base-pair mtDNA deletion and a TT-to-AA mutation. Next-nucleotide effects and dislocation mutagenesis may contribute to the formation of these mutations. These results provide the first demonstration that alterations of nucleoside metabolism can induce multiple sequence-specific point mutations in humans. We hypothesize that, in patients with TP deficiency, increased levels of dThd and dUrd cause mitochondrial nucleotide pool imbalances, which, in turn, lead to mtDNA abnormalities including site-specific point mutations

show abstract

mentioning

confidence: 99%

Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

Nishigaki¹,

Martí²,

Copeland³

et al. 2003

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…A similar effect is seen in progressive external ophthalmoplegia, a disease which is characterized by the formation of a variety of mtDNA deletions throughout the patient's lifetime. These deletions were found to vary from cell to cell, showing clonal expansion (99). Yet another disease state with possible implications for the interpretation of data concerning the common deletion in aging is Hashimoto's thyroiditis.…”

Section: Relationship Between Deletions and Oxidative Damagementioning

confidence: 98%

Mitochondria, oxidative DNA damage, and aging

Anson

Bohr

2000

AGE

View full text Add to dashboard Cite

Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, MnSOD -/+ mice incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences.

show abstract

“…Clearly, in the case of homoplasmic mtDNA mutation, the aberrant mitochondrial gene(s) involved will be the only ones that are expressed. The appearance of altered RNA and protein products may distort cell homeostasis and therefore be harmful and pathogenic as seen in mitochondrial diseases [45][46][47][48]. More obscure situations arise when the mtDNA mutation is heteroplasmic and occurs concomitantly with wild-type mitochondrial genome.…”

Section: Structure and Biological Properties Of Mtdnamentioning

confidence: 99%

Mitochondrial DNA and Human Thyroid Diseases

2004

View full text Add to dashboard Cite

Abstract. Cells of the thyroid tissue, either diseased or normal, can accumulate altered mitochondrial genomes in primary lesions and in surrounding parenchyma. Depending on the experimental approaches and the extent of the mutational process, it has been possible to demonstrate the occurrence of homoplasmic or heteroplasmic point mutations, presence of a common deletion and random large-scale mtDNA aberrations in various pathological states. Point somatic mutations documented in 5-60% of thyroid tumors do not concentrate in obvious hotspots but tend to cluster in certain regions of the mitochondrial genome and their distribution may differ between carcinomas and controls. Large-scale deletions in mtDNA are quite prevalent in healthy and diseased thyroid; however, the proportion of aberrant mtDNA molecules accounts for a very small part of total mtDNA and does not seem to correlate with pathological characteristics of thyroid tumors. Common deletion is most abundant in Hurthle cell tumors, yet it also occurs in other thyroid diseases as well as in normal tissue. The principal difference between the common deletion and other deletion-type mtDNA molecules is that the former does not depend on the relative mtDNA content in the tissue whereas in a subset of thyroid tumors, such as radiation-associated papillary carcinomas and follicular adenomas, there is a strong correlation between mtDNA levels and prevalence of large-scale deletions. Relative mtDNA levels by themselves are elevated in most thyroid tumors compared to normal tissue. Distinct differential distribution and prevalence of mutational mtDNA burden in normal tissue and thyroid lesions are suggestive of the implication of altered mtDNA in thyroid diseases, especially in cancer.

show abstract

Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia

Cited by 86 publications

References 35 publications

Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

Mitochondria, oxidative DNA damage, and aging

Mitochondrial DNA and Human Thyroid Diseases

Contact Info

Product

Resources

About