Mitochondria as determinant of nucleotide pools and chromosomal stability.
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.
Desler
Claus
C
Department of Science, Systems and Models, Roskilde University, 4000 Roskilde, Denmark.
Munch-Petersen
Birgitte
B
Stevnsner
Tinna
T
Matsui
Sei-Ichi
S
Kulawiec
Mariola
M
Singh
Keshav K
KK
Rasmussen
Lene Juel
LJ
D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D020552:Comet Assay; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015162:Micronucleus Tests; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D013942:Thymine Nucleotides / Q000378:metabolism
D004272:DNA, Mitochondrial; D003854:Deoxyribonucleotides; D013942:Thymine Nucleotides