Mitochondria as determinant of nucleotide pools and chromosomal stability

TY - JOUR

T1 - Mitochondria as determinant of nucleotide pools and chromosomal stability

AU - Desler, Claus

AU - Munch-Petersen, Birgitte

AU - Stevnsner, Tinna

AU - Matsui, Sei-Ichi

AU - Kulawiec, Mariola

AU - Singh, Keshav K

AU - Rasmussen, Lene Juel

PY - 2007/12/1

Y1 - 2007/12/1

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 - Chromosomal Instability

KW - Comet Assay

KW - DNA Repair

KW - DNA, Mitochondrial

KW - Deoxyribonucleotides

KW - HeLa Cells

KW - Humans

KW - Micronucleus Tests

KW - Mitochondria

KW - Thymine Nucleotides

U2 - 10.1016/j.mrfmmm.2007.06.002

DO - 10.1016/j.mrfmmm.2007.06.002

M3 - Journal article

C2 - 17658559

SN - 0027-5107

VL - 625

SP - 112

EP - 124

JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

IS - 1-2

ER -