Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

Spelbrink, Johannes N.; Zwart, Rob; Galen, M. J. M. Van; Bogert, Coby Van den

doi:10.1007/s002940050255

Cited by 17 publications

(9 citation statements)

References 42 publications

(68 reference statements)

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“…24 Upon removal of the doxycycline, the proportion of deleted mtDNA rapidly increased up to approximately the original level. The behaviour of deleted mtDNA before, during and after doxycycline treatment suggested that the percentage of mutant mtDNA is a balance between its preferential amplification and its phenotypic disadvantage.…”

Section: Discussionmentioning

confidence: 99%

“…The behaviour of deleted mtDNA before, during and after doxycycline treatment suggested that the percentage of mutant mtDNA is a balance between its preferential amplification and its phenotypic disadvantage. 24 Despite the fact that mitochondrial protein synthesis is clearly affected leading to metabolic disadvantage to cells, no selection against deleted mtDNA occurs in our cybrid cells containing 80% of deleted mtDNA. Rather, the percentage of 80% of deleted mtDNA is maintained, or might even be slowly increasing, ultimately leading to a disturbance in mtDNA copy number control by the osteosarcoma nuclear background through the operation of a yet unknown mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Also, in a lymphoblast cell line derived from a patient with Pearson syndrome a heteroplasmy level of 60-70% deleted mtDNA was maintained over a 4-year period of continuous cell proliferation. 24 Others have reported the preferential accumulation of deleted mtDNA over wild-type mtDNA in HeLa-cell derived cybrid cells. 11 Altogether, these mtDNA deletion in Pearson syndrome JMW van den Ouweland et al y data indicate that segregation of deleted mtDNA may, or may not occur depending on the nuclear background of the cell containing deleted mtDNA.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow–pancreas syndrome

et al. 2000

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We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed DNA analysis to seek for deletions in mtDNA. DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of 0 cells we could show inter-as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow–pancreas syndrome

et al. 2000

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“…These nuclear mutations may exclusively drive clonal expansion toward leukemia. Therefore, functionally relevant mutations of mtDNA, found in neoplasms, may contribute to carcinogenesis in a "pseudoclonal" way (1,25), because they represent a growth handicap to the proliferating cells (35). Clonal expansion may now lead in an epiphenomenal, stochastic way (36) to mitochondrial outgrowth and may even explain why polymorphisms evolve by random drift to homoplasmy.…”

Section: Apoptosis In Mdsmentioning

confidence: 99%

Comprehensive Scanning of Somatic Mitochondrial DNA Alterations in Acute Leukemia Developing from Myelodysplastic Syndromes

2004

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“…Mitochondria also lack some of the DNA repair pathways that operate in the nucleus to reduce mutation rates (6). However, some defects may accumulate because mutant mitochondrial chromosomes have a fitness advantage over functional mitochondrial genomes within cells (7)(8)(9)(10)(11)(12)(13)(14). The opportunity for natural selection to occur within cells stems from the fact that each cell contains multiple mitochondrial genomes that replicate independently of the cell.…”

mentioning

confidence: 99%

Conflicting levels of selection in the accumulation of mitochondrial defects in Saccharomyces cerevisiae

Taylor

Zeyl

Cooke

2002

Proc. Natl. Acad. Sci. U.S.A.

114

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The somatic accumulation of defective mitochondria causes human degenerative syndromes, senescence in fungi, and male sterility in plants. These diverse phenomena may result from conflicts between natural selection at different levels of organization. Such conflicts are fundamental to the evolution of cooperating groups, from cells to populations. We present a model in which defective mitochondrial genomes accumulate because of a within-cell replication advantage when among-cell selection for efficient respiration is relaxed. We tested the model by using experimental populations of the yeast Saccharomyces cerevisiae. We constructed yeast strains that were heteroplasmic for mitochondrial mutations that destroy the ability to respire (the petite phenotype) and followed the accumulation of mitochondrial defects in cultures with different effective population sizes. As predicted by the model, the inability to respire evolved only in small populations of S. cerevisiae, where among-cell selection favoring cells that can respire was reduced relative to within-cell selection favoring parasitic mitochondria. In a control experiment, mitochondrial point mutations that confer resistance to chloramphenicol showed no tendency to change in frequency under any culture conditions. The accumulation of some mitochondrial defects is therefore an evolutionary process, involving multiple levels of selection. The relative intensities of within-and among-cell selection may also explain the tissue specificity of human mitochondrial defects.

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Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

Cited by 17 publications

References 42 publications

Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow–pancreas syndrome

Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow–pancreas syndrome

Comprehensive Scanning of Somatic Mitochondrial DNA Alterations in Acute Leukemia Developing from Myelodysplastic Syndromes

Conflicting levels of selection in the accumulation of mitochondrial defects in Saccharomyces cerevisiae

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