TY - JOUR
T1 - Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias
AU - Hämäläinen, Riikka H.
AU - Landoni, Juan C.
AU - Ahlqvist, Kati J.
AU - Goffart, Steffi
AU - Ryytty, Sanna
AU - Rahman, M. Obaidur
AU - Brilhante, Virginia
AU - Icay, Katherine
AU - Hautaniemi, Sampsa
AU - Wang, Liya
AU - Laiho, Marikki
AU - Suomalainen, Anu
N1 - Funding Information:
We thank T. Manninen, H. Ojala, M. Innilä and A. Muranen (University of Helsinki) for technical assistance, C. Storgaard Sørensen and K. Voßgröne (University of Copenhagen) for technical advice and T. McWilliams, C. Dunn and K. Wartiovaara (University of Helsinki) for discussion and critical comments. This work was supported by the Academy of Finland (275215 to R.H.H., 307592 to A.S., 303349 A.S., 30743 to A.S.), the Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, the University of Helsinki, the University of Eastern Finland and the European Research Council (268955 to A.S.).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5′-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism for mouse progerias. Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited.
AB - Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5′-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism for mouse progerias. Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited.
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U2 - 10.1038/s42255-019-0120-1
DO - 10.1038/s42255-019-0120-1
M3 - Letter
C2 - 32694840
AN - SCOPUS:85074080154
SN - 2522-5812
VL - 1
SP - 958
EP - 965
JO - Nature Metabolism
JF - Nature Metabolism
IS - 10
ER -