Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice

Emil Ylikallio, Jennifer L. Page, Xia Xu, Milla Lampinen, Gerold Bepler, Tomomi Ide, Henna Tyynismaa, Robert S. Weiss, Anu Suomalainen

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles in nuclear genome maintenance. RNR is also essential for maintenance of mitochondrial DNA (mtDNA) in mammals. The mechanisms regulating mtDNA copy number in mammals are only being discovered. In budding yeast, RNR overexpression resulted in increased mtDNA levels, and rescued the disease phenotypes caused by a mutant mtDNA polymerase. This raised the question of whether mtDNA copy number increase by RNR induction could be a strategy for treating diseases with mtDNA mutations. We show here that high-level overexpression of RNR subunits (Rrm1, Rrm2 and p53R2; separately or in different combinations) in mice does not result in mtDNA copy number elevation. Instead, simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis. We also show that endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear-mitochondrial crosstalk with regard to mtDNA copy number. Our results establish that RNR is not limiting for mtDNA copy number in mice, and provide new evidence for the importance of balanced dNTP pools in mtDNA maintenance in postmitotic tissues.

Original languageEnglish
Pages (from-to)8208-8218
Number of pages11
JournalNucleic acids research
Volume38
Issue number22
DOIs
Publication statusPublished - Dec 1 2010

Fingerprint

Ribonucleotide Reductases
Mitochondrial DNA
Deoxyribonucleosides
Maintenance
Mammals
Saccharomycetales
DNA-Directed DNA Polymerase
Mutagenesis

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Ylikallio, E., Page, J. L., Xu, X., Lampinen, M., Bepler, G., Ide, T., ... Suomalainen, A. (2010). Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice. Nucleic acids research, 38(22), 8208-8218. https://doi.org/10.1093/nar/gkq735

Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice. / Ylikallio, Emil; Page, Jennifer L.; Xu, Xia; Lampinen, Milla; Bepler, Gerold; Ide, Tomomi; Tyynismaa, Henna; Weiss, Robert S.; Suomalainen, Anu.

In: Nucleic acids research, Vol. 38, No. 22, 01.12.2010, p. 8208-8218.

Research output: Contribution to journalArticle

Ylikallio, E, Page, JL, Xu, X, Lampinen, M, Bepler, G, Ide, T, Tyynismaa, H, Weiss, RS & Suomalainen, A 2010, 'Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice', Nucleic acids research, vol. 38, no. 22, pp. 8208-8218. https://doi.org/10.1093/nar/gkq735
Ylikallio, Emil ; Page, Jennifer L. ; Xu, Xia ; Lampinen, Milla ; Bepler, Gerold ; Ide, Tomomi ; Tyynismaa, Henna ; Weiss, Robert S. ; Suomalainen, Anu. / Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice. In: Nucleic acids research. 2010 ; Vol. 38, No. 22. pp. 8208-8218.
@article{f94e4130330348329f1b1d47a7855356,
title = "Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice",
abstract = "Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles in nuclear genome maintenance. RNR is also essential for maintenance of mitochondrial DNA (mtDNA) in mammals. The mechanisms regulating mtDNA copy number in mammals are only being discovered. In budding yeast, RNR overexpression resulted in increased mtDNA levels, and rescued the disease phenotypes caused by a mutant mtDNA polymerase. This raised the question of whether mtDNA copy number increase by RNR induction could be a strategy for treating diseases with mtDNA mutations. We show here that high-level overexpression of RNR subunits (Rrm1, Rrm2 and p53R2; separately or in different combinations) in mice does not result in mtDNA copy number elevation. Instead, simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis. We also show that endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear-mitochondrial crosstalk with regard to mtDNA copy number. Our results establish that RNR is not limiting for mtDNA copy number in mice, and provide new evidence for the importance of balanced dNTP pools in mtDNA maintenance in postmitotic tissues.",
author = "Emil Ylikallio and Page, {Jennifer L.} and Xia Xu and Milla Lampinen and Gerold Bepler and Tomomi Ide and Henna Tyynismaa and Weiss, {Robert S.} and Anu Suomalainen",
year = "2010",
month = "12",
day = "1",
doi = "10.1093/nar/gkq735",
language = "English",
volume = "38",
pages = "8208--8218",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "22",

}

TY - JOUR

T1 - Ribonucleotide reductase is not limiting for mitochondrial DNA copy number in mice

AU - Ylikallio, Emil

AU - Page, Jennifer L.

AU - Xu, Xia

AU - Lampinen, Milla

AU - Bepler, Gerold

AU - Ide, Tomomi

AU - Tyynismaa, Henna

AU - Weiss, Robert S.

AU - Suomalainen, Anu

PY - 2010/12/1

Y1 - 2010/12/1

N2 - Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles in nuclear genome maintenance. RNR is also essential for maintenance of mitochondrial DNA (mtDNA) in mammals. The mechanisms regulating mtDNA copy number in mammals are only being discovered. In budding yeast, RNR overexpression resulted in increased mtDNA levels, and rescued the disease phenotypes caused by a mutant mtDNA polymerase. This raised the question of whether mtDNA copy number increase by RNR induction could be a strategy for treating diseases with mtDNA mutations. We show here that high-level overexpression of RNR subunits (Rrm1, Rrm2 and p53R2; separately or in different combinations) in mice does not result in mtDNA copy number elevation. Instead, simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis. We also show that endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear-mitochondrial crosstalk with regard to mtDNA copy number. Our results establish that RNR is not limiting for mtDNA copy number in mice, and provide new evidence for the importance of balanced dNTP pools in mtDNA maintenance in postmitotic tissues.

AB - Ribonucleotide reductase (RNR) is the rate-limiting enzyme in deoxyribonucleoside triphosphate (dNTP) biosynthesis, with important roles in nuclear genome maintenance. RNR is also essential for maintenance of mitochondrial DNA (mtDNA) in mammals. The mechanisms regulating mtDNA copy number in mammals are only being discovered. In budding yeast, RNR overexpression resulted in increased mtDNA levels, and rescued the disease phenotypes caused by a mutant mtDNA polymerase. This raised the question of whether mtDNA copy number increase by RNR induction could be a strategy for treating diseases with mtDNA mutations. We show here that high-level overexpression of RNR subunits (Rrm1, Rrm2 and p53R2; separately or in different combinations) in mice does not result in mtDNA copy number elevation. Instead, simultaneous expression of two RNR subunits leads to imbalanced dNTP pools and progressive mtDNA depletion in the skeletal muscle, without mtDNA mutagenesis. We also show that endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear-mitochondrial crosstalk with regard to mtDNA copy number. Our results establish that RNR is not limiting for mtDNA copy number in mice, and provide new evidence for the importance of balanced dNTP pools in mtDNA maintenance in postmitotic tissues.

UR - http://www.scopus.com/inward/record.url?scp=78650493661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650493661&partnerID=8YFLogxK

U2 - 10.1093/nar/gkq735

DO - 10.1093/nar/gkq735

M3 - Article

C2 - 20724444

AN - SCOPUS:78650493661

VL - 38

SP - 8208

EP - 8218

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 22

ER -