Construction of Transgenic Mice with Tissue-Specific Acceleration of Mitochondrial DNA Mutagenesis

Zhang, Dekui; Mott, Justin L.; Chang, Shin Wen; Denniger, Grace; Feng, Zhanlian; Zassenhaus, Hans Peter

doi:10.1006/geno.2000.6333

Cited by 117 publications

(96 citation statements)

References 38 publications

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“…Inhibition of pol ␥ proofreading by monophosphates or inactivation of exonuclease activity results in as much as a 20-fold decrease in replication fidelity in vitro (39,40). 2 In vivo, the exonuclease-deficient yeast and mouse DNA polymerase ␥ transgenes have conferred a mutator phenotype in mitochondrial DNA (41,42). Thus, inhibition of pol ␥ exonuclease function by AZT-MP is likely to result in mutations within the mitochondrial DNA.…”

Section: Resultsmentioning

confidence: 99%

Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ

Lim

Copeland

2001

Journal of Biological Chemistry

214

182

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Mitochondrial toxicity can result from antiviral nucleotide analog therapy used to control human immunodeficiency virus type 1 infection. We evaluated the ability of such analogs to inhibit DNA synthesis by the human mitochondrial DNA polymerase (pol ␥) by comparing the insertion and exonucleolytic removal of six antiviral nucleotide analogs. Apparent steady-state K m and k cat values for insertion of 2,3-dideoxy-TTP (ddTTP), 3-azido-TTP (AZT-TP), 2,3-dideoxy-CTP (ddCTP), 2,3-didehydro-TTP (D4T-TP), (-)-2,3-dideoxy-3-thiacytidine (3TC-TP), and carbocyclic 2,3-didehydro-ddGTP (CBV-TP) indicated incorporation of all six analogs, albeit with varying efficiencies. Dideoxynucleotides and D4T-TP were utilized by pol ␥ in vitro as efficiently as natural deoxynucleotides, whereas AZT-TP, 3TC-TP, and CBV-TP were only moderate inhibitors of DNA chain elongation. Inefficient excision of dideoxynucleotides, D4T, AZT, and CBV from DNA predicts persistence in vivo following successful incorporation. In contrast, removal of 3-terminal 3TC residues was 50% as efficient as natural 3 termini. Finally, we observed inhibition of exonuclease activity by concentrations of AZT-monophosphate known to occur in cells. Thus, although their greatest inhibitory effects are through incorporation and chain termination, persistence of these analogs in DNA and inhibition of exonucleolytic proofreading may also contribute to mitochondrial toxicity.More than 36 million people are infected by the human immunodeficiency virus worldwide, where 5.3 million new infections occurred during 2000 (1). Although antiviral therapy effectively extends the life of individuals, the death toll continues to rise; 3 million people, the highest number since the epidemic began, died from AIDS in 2000 (1). Nucleoside analogs utilized in antiviral therapy are readily incorporated into DNA by the HIV-1 1 reverse transcriptase. Although viral replication is effectively inhibited by DNA chain terminators, cellular side effects also result. The continuous antiviral therapy required to keep the HIV infection under control has increased the chance for severe antiviral analog induced toxicity. Current antiviral nucleoside analog therapy against HIV clearly results in compromised mitochondrial function due to inhibition of the mitochondrial DNA polymerase (2, 3).AZT was the first analog to be approved for anti-HIV therapy in 1985 were the first to report mitochondrial myopathies in HIV-infected individuals undergoing AZT treatment. Control studies thereafter demonstrated that these induced myopathies, most notably visualized histologically as ragged red fibers, were indeed caused by AZT treatment and were not a consequence of the HIV infection (5). This study revealed reduced amounts of mitochondrial DNA in AZT-treated skeletal muscle (5). Further clinical evidence has demonstrated that mitochondrial myopathy slowly and cumulatively develops during AZT treatment (6).The second class of antiviral nucleoside analogs approved for HIV therapy are the dideoxynucleoside analogs ddI...

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Section: Resultsmentioning

confidence: 99%

Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ

Lim

Copeland

2001

Journal of Biological Chemistry

214

182

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“…Inactivation of OGG1 leads to the accumulation of point mutations and deletion mutations in mtDNA (Singh et al, 2001). Polymerase γ is another key enzyme in the repair of 8-oxo-G lesions in the DNA induced by ROS, and transgenic mice expressing a proofreading-deficient polymerase γ exhibit accumulation of point and deletion mutations in mtDNA (Zhang et al, 2000). To protect against the effects of ROS, mitochondria metabolize superoxide and hydrogen peroxide with MnSOD and Se-containing glutathione peroxidase, respectively.…”

Section: Causes For Mtdna Depletion and Deletionmentioning

confidence: 99%

Regulation of mitochondrial DNA content and cancer

Higuchi

2007

Mitochondrion

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Enzymatic activities of the proteins encoded in nuclear genome are regulated by transcriptional, translational and post-transcriptional level. Enzymatic activities of proteins encoded in mitochondrial DNA (mtDNA) have been considered to be regulated by the same steps although detailed mechanisms might differ. However, dynamic change of the number of mtDNA, from some hundred to more than ten thousand, should be considered as another novel mechanism to regulate mtDNA-encoded proteins. Recently, we showed the connection of mtDNA depletion and deletion to cancer progression (Higuchi et al., 2006). This review focuses and describes the possible connections of the mitochondrial DNA depletion and deletion to cancer.

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“…The expected incidence of point mutations apparently significantly exceeds that of deletions and approaches one per mtDNA copy, thus making clonal accumulation of point mutations in mtDNA an attractive potential aging mechanism. Interestingly, a high rate of somatic point mutations in a transgenic mouse expressing an error-prone mtDNA polymerase gamma in the heart resulted in a severe, early onset cardiomyopathy (19).…”

mentioning

confidence: 99%

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

Nekhaeva

Bodyak

Kraytsberg

et al. 2002

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

192

113

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Using single-cell sequence analysis, we discovered that a high proportion of cells in tissues as diverse as buccal epithelium and heart muscle contain high proportions of clonal mutant mtDNA expanded from single initial mutant mtDNA molecules. We demonstrate that intracellular clonal expansion of somatic point mutations is a common event in normal human tissues. This finding implies efficient homogenization of mitochondrial genomes within individual cells. Significant qualitative differences observed between the spectra of clonally expanded mutations in proliferating epithelial cells and postmitotic cardiomyocytes suggest, however, that either the processes generating these mutations or mechanisms driving them to homoplasmy are likely to be fundamentally different between the two tissues. Furthermore, the ability of somatic mtDNA mutations to expand (required for their phenotypic expression), as well as their apparently high incidence, reinforces the possibility that these mutations may be involved actively in various physiological processes such as aging and degenerative disease. The abundance of clonally expanded point mutations in individual cells of normal tissues also suggests that the recently discovered accumulation of mtDNA mutations in tumors may be explained by processes that are similar or identical to those operating in the normal tissue. somatic mutation ͉ clonal expansion ͉ single cell ͉ aging ͉ cancer

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Construction of Transgenic Mice with Tissue-Specific Acceleration of Mitochondrial DNA Mutagenesis

Cited by 117 publications

References 38 publications

Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ

Differential Incorporation and Removal of Antiviral Deoxynucleotides by Human DNA Polymerase γ

Regulation of mitochondrial DNA content and cancer

Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

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