A tandem duplication in the D–loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies

Brockington, M; Mg, Sweeney; Hammans,; Ja, Morgan-Hughes; Harding, A E

doi:10.1038/ng0593-67

Cited by 68 publications

(43 citation statements)

References 21 publications

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“…This was associated with instability in the number of C's in a homopolymeric string starting at nt 568 (Wu et al 2005). Interestingly, this same duplication was found to be a characteristic of European haplogroup I (Torroni et al 1994) and has been implicated in predisposition to mtDNA rearrangements (Brockington et al 1993). The presence of similar mtDNA control region mutations in tumors and populations raises the possibility that the mitochondria may be exposed to similar selective forces in both populations and tissues.…”

Section: Mitochondrial Pathophysiology Of Aging and Cancermentioning

confidence: 94%

Mitochondria and Cancer: Warburg Addressed

Wallace¹

2005

Cold Spring Harbor Symposia on Quantitative Biology

245

174

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Otto Warburg recognized that cancer cells generate excessive lactate in the presence of oxygen (aerobic glycolysis). It now appears that this phenomenon is the product of two factors: a return to the more glycolytic metabolism of the embryo and alterations in oxidative phosphorylation (OXPHOS) to increase mitochondrial reactive oxygen species (ROS) production. Alterations in the Ras-PI3K-Akt signal transduction pathway can result in induction of hexokinase II and its attachment to mitochondrial porin redirecting mitochondrial ATP to phosphorylate glucose and drive glycolysis. Furthermore, partial inhibition of OXPHOS by mitochondrial gene mutations (germ-line or somatic) can reduce electron flux through the electron transport chain, increasing mitochondrial ROS production. The increased ROS mutagenizes nuclear proto-oncogenes (initiation) and drives nuclear replication (promotion), resulting in cancer. Therefore, hexokinase II and mitochondrial ROS may be useful alternate targets for cancer therapeutics.

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Section: Mitochondrial Pathophysiology Of Aging and Cancermentioning

confidence: 94%

Mitochondria and Cancer: Warburg Addressed

Wallace¹

2005

Cold Spring Harbor Symposia on Quantitative Biology

245

174

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“…This was associated with instability in the number of Cs in a homopolymeric string starting at nt 568 (Wu et al, 2005). This same duplication was found to be a characteristic of European haplogroup I (Torroni et al, 1994) and has been implicated in predisposition to mtDNA rearrangements (Brockington et al, 1993).…”

Section: Brandon Et Almentioning

confidence: 97%

Mitochondrial mutations in cancer

2006

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“…There has been a suggested link between the presence of the common deletion and tandem duplications in the D-loop (Brockington et al, 1993). Two of the seven NMSC patients, who harboured high levels of the common deletion, also contained either a 200 or 260 bp tandem duplication.…”

Section: The 4977 Bp Common Mtdna Deletion and Tandem Duplicationsmentioning

confidence: 99%

“…Under the designated PCR conditions, the orientation of these primers prevents the generation of a product from wild-type mtDNA but permits a product from mitochondrial genomes harbouring a 200 bp or a 260 bp tandem duplication in the D-loop. The nucleotide positions of the tandem duplication breakpoints have been previously described (Brockington et al, 1993;Lee et al, 1994).…”

Section: -Primer Pcrmentioning

confidence: 99%

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Mitochondrial DNA damage in non-melanoma skin cancer

et al. 2003

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Mitochondrial DNA (mtDNA) damage, predominantly encompassing point mutations, has been reported in a variety of cancers. Here we present in human skin, the first detailed study of the distribution of multiple forms of mtDNA damage in nonmelanoma skin cancer (NMSC) compared to histologically normal perilesional dermis and epidermis. We present the first entire spectrum of deletions found between different types of skin tumours and perilesional skin. In addition, we provide the first quantitative data for the incidence of the common deletion as well as the first report of specific tandem duplications in tumours from any tissue. Importantly, this work shows that there are clear differences in the distribution of deletions between the tumour and the histologically normal perilesional skin. Furthermore, DNA sequencing of four mutation 'hotspot' regions of the mitochondrial genome identified a previously unreported somatic heteroplasmic mutation in an SCC patient. In addition, 81 unreported and reported homoplasmic single base changes were identified in the other NMSC patients. Unlike the distribution of deletions and the heteroplasmic mutation, these homoplasmic mutations were present in both tumour and perilesional skin, which suggests that for some genetic studies the traditional use of histologically normal perilesional skin from NMSC patients may be limited. Currently, it is unclear whether mtDNA damage has a direct link to skin cancer or it may simply reflect an underlying nuclear DNA instability.

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A tandem duplication in the D–loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies

Cited by 68 publications

References 21 publications

Mitochondria and Cancer: Warburg Addressed

Mitochondria and Cancer: Warburg Addressed

Mitochondrial mutations in cancer

Mitochondrial DNA damage in non-melanoma skin cancer

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