Mitochondria as determinant of nucleotide pools and chromosomal stability

Claus Desler Madsen, Birgitte Munch-Petersen, Tinna Stevnsner, Sei-Ichi Matsui, Keshav Singh, Mariola Kulawiec, Lene Juel Rasmussen

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Mitochondrial function plays an important role in multiple human diseases and mutations in the mitochondrial genome have been detected in nearly every type of cancer investigated to date. However, the mechanism underlying the interrelation is unknown. We used human cell lines depleted of mitochondrial DNA as models and analyzed the outcome of mitochondrial dysfunction on major cellular repair activities. We show that the deoxyribonucleoside triphosphate (dNTP) pools are affected, most prominently we detect a 3-fold reduction of the dTTP pool when normalized to the number of cells in S-phase. It is known that imbalanced dNTP pools are mutagenic and in accordance, we show that mitochondrial dysfunction results in chromosomal instability, which can explain its role in tumor development. We did not find any straightforward correlation between ATP levels and dNTP pools in cells with defective mitochondrial activity. Our results suggest that mitochondria are central players in maintaining genomic stability and in controlling essential nuclear processes such as upholding a balanced supply of nucleotides.
    Original languageEnglish
    JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
    Volume625
    Issue number1-2
    Pages (from-to)112-124
    Number of pages13
    ISSN0027-5107
    DOIs
    Publication statusPublished - 2007

    Keywords

    • Mitochondrial disease
    • Cancer
    • Chromosomal instability
    • DNA repair
    • dNTP levels

    Cite this

    Madsen, Claus Desler ; Munch-Petersen, Birgitte ; Stevnsner, Tinna ; Matsui, Sei-Ichi ; Singh, Keshav ; Kulawiec, Mariola ; Rasmussen, Lene Juel. / Mitochondria as determinant of nucleotide pools and chromosomal stability. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2007 ; Vol. 625, No. 1-2. pp. 112-124.
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    title = "Mitochondria as determinant of nucleotide pools and chromosomal stability",
    abstract = "Mitochondrial function plays an important role in multiple human diseases and mutations in the mitochondrial genome have been detected in nearly every type of cancer investigated to date. However, the mechanism underlying the interrelation is unknown. We used human cell lines depleted of mitochondrial DNA as models and analyzed the outcome of mitochondrial dysfunction on major cellular repair activities. We show that the deoxyribonucleoside triphosphate (dNTP) pools are affected, most prominently we detect a 3-fold reduction of the dTTP pool when normalized to the number of cells in S-phase. It is known that imbalanced dNTP pools are mutagenic and in accordance, we show that mitochondrial dysfunction results in chromosomal instability, which can explain its role in tumor development. We did not find any straightforward correlation between ATP levels and dNTP pools in cells with defective mitochondrial activity. Our results suggest that mitochondria are central players in maintaining genomic stability and in controlling essential nuclear processes such as upholding a balanced supply of nucleotides.",
    keywords = "Kr{\ae}ft, Mitochondrial disease, Cancer, Chromosomal instability, DNA repair, dNTP levels",
    author = "Madsen, {Claus Desler} and Birgitte Munch-Petersen and Tinna Stevnsner and Sei-Ichi Matsui and Keshav Singh and Mariola Kulawiec and Rasmussen, {Lene Juel}",
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    Mitochondria as determinant of nucleotide pools and chromosomal stability. / Madsen, Claus Desler; Munch-Petersen, Birgitte; Stevnsner, Tinna; Matsui, Sei-Ichi; Singh, Keshav; Kulawiec, Mariola; Rasmussen, Lene Juel.

    In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 625, No. 1-2, 2007, p. 112-124.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Mitochondria as determinant of nucleotide pools and chromosomal stability

    AU - Madsen, Claus Desler

    AU - Munch-Petersen, Birgitte

    AU - Stevnsner, Tinna

    AU - Matsui, Sei-Ichi

    AU - Singh, Keshav

    AU - Kulawiec, Mariola

    AU - Rasmussen, Lene Juel

    N1 - Paper id:: 17658559

    PY - 2007

    Y1 - 2007

    N2 - Mitochondrial function plays an important role in multiple human diseases and mutations in the mitochondrial genome have been detected in nearly every type of cancer investigated to date. However, the mechanism underlying the interrelation is unknown. We used human cell lines depleted of mitochondrial DNA as models and analyzed the outcome of mitochondrial dysfunction on major cellular repair activities. We show that the deoxyribonucleoside triphosphate (dNTP) pools are affected, most prominently we detect a 3-fold reduction of the dTTP pool when normalized to the number of cells in S-phase. It is known that imbalanced dNTP pools are mutagenic and in accordance, we show that mitochondrial dysfunction results in chromosomal instability, which can explain its role in tumor development. We did not find any straightforward correlation between ATP levels and dNTP pools in cells with defective mitochondrial activity. Our results suggest that mitochondria are central players in maintaining genomic stability and in controlling essential nuclear processes such as upholding a balanced supply of nucleotides.

    AB - Mitochondrial function plays an important role in multiple human diseases and mutations in the mitochondrial genome have been detected in nearly every type of cancer investigated to date. However, the mechanism underlying the interrelation is unknown. We used human cell lines depleted of mitochondrial DNA as models and analyzed the outcome of mitochondrial dysfunction on major cellular repair activities. We show that the deoxyribonucleoside triphosphate (dNTP) pools are affected, most prominently we detect a 3-fold reduction of the dTTP pool when normalized to the number of cells in S-phase. It is known that imbalanced dNTP pools are mutagenic and in accordance, we show that mitochondrial dysfunction results in chromosomal instability, which can explain its role in tumor development. We did not find any straightforward correlation between ATP levels and dNTP pools in cells with defective mitochondrial activity. Our results suggest that mitochondria are central players in maintaining genomic stability and in controlling essential nuclear processes such as upholding a balanced supply of nucleotides.

    KW - Kræft

    KW - Mitochondrial disease

    KW - Cancer

    KW - Chromosomal instability

    KW - DNA repair

    KW - dNTP levels

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    DO - 10.1016/j.mrfmmm.2007.06.002

    M3 - Journal article

    VL - 625

    SP - 112

    EP - 124

    JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

    JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

    SN - 0027-5107

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    ER -