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Cited by 195

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Random Point Mutations with Major Effects on Protein-Coding Genes Are the Driving Force behind Premature Aging in mtDNA Mutator Mice

Edgar, Daniel, Shabalina, Irina, Camara, Yolanda, Wredenberg, Anna, Calvaruso, Maria Antonietta, Nijtmans, Leo, Nedergaard, Jan, Cannon, Barbara, Larsson, Nils-Göran, Trifunovic, Aleksandra·2009·Cell Metabolism
DOI 10.1016/j.cmet.2009.06.010
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Abstract

The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.

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Crossref · 10.1016/j.cmet.2009.06.010

Cites

3 of 3 references verified0 citation errors · 0 not checkable

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  • Cells from mice deficient in mitochondrial DNA polymerase γ show impaired mitochondrial function but this is not accompanied by increased ROS production.

    “Cells from these mice show impaired mitochondrial function but, unexpectedly, this is not accompanied by increased ROS production (Edgar et al., 2009; Hiona et al., 2010).”

    From The Hallmarks of Aging (2013) · cites this paper as Edgar et al., 2009

  • Dysfunctional mitochondria can contribute to aging independently of ROS, as exemplified by studies with mice deficient in DNA polymerase γ.

    “Dysfunctional mitochondria can contribute to aging independently of ROS, as exemplified by studies with mice deficient in DNA polymerase γ”

    From The Hallmarks of Aging (2013) · cites this paper as Edgar et al., 2009

  • In mice, genetic manipulations that impair mitochondrial function but do not increase ROS accelerate aging.

    “genetic manipulations that impair mitochondrial function but do not increase ROS accelerate aging”

    From The Hallmarks of Aging (2013) · cites this paper as Edgar et al., 2009

Citations

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Research works printed but not linked: 23

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  2. Cote, 1989, Expression of the mammalian mitochondrial genome. Stability of mitochondrial translation products as a function of membrane potential, J. Biol. Chem., 264, 8487
  3. Fayet, 2002, Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function, Neuromuscul. Disord., 12, 484, 10.1016/S0960-8966(01)00332-7 · DOI · Paper page
  4. Hayashi, 1991, Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction, Proc. Natl. Acad. Sci. USA, 88, 10614, 10.1073/pnas.88.23.10614 · DOI
  5. Holt, 1988, Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies, Nature, 331, 717, 10.1038/331717a0 · DOI
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  7. Lamantea, 2002, A novel nonsense mutation (Q352X) in the mitochondrial cytochrome b gene associated with a combined deficiency of complexes I and III, Neuromuscul. Disord., 12, 49, 10.1016/S0960-8966(01)00244-9 · DOI
  8. Li, 2007, An assembled complex IV maintains the stability and activity of complex I in mammalian mitochondria, J. Biol. Chem., 282, 17557, 10.1074/jbc.M701056200 · DOI
  9. Metodiev, 2009, Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome, Cell Metab., 9, 386, 10.1016/j.cmet.2009.03.001 · DOI
  10. Nijtmans, 2002, Blue Native electrophoresis to study mitochondrial and other protein complexes, Methods, 26, 327, 10.1016/S1046-2023(02)00038-5 · DOI
  11. Niu, 2007, Somatic mtDNA mutations cause progressive hearing loss in the mouse, Exp. Cell Res., 313, 3924, 10.1016/j.yexcr.2007.05.029 · DOI
  12. Park, 2007, MTERF3 is a negative regulator of mammalian mtDNA transcription, Cell, 130, 273, 10.1016/j.cell.2007.05.046 · DOI
  13. Saraste, 1990, Structural features of cytochrome oxidase, Q. Rev. Biophys., 23, 331, 10.1017/S0033583500005588 · DOI
  14. Shabalina, 2006, UCP1 and defense against oxidative stress. 4-Hydroxy-2-nonenal effects on brown fat mitochondria are uncoupling protein 1-independent, J. Biol. Chem., 281, 13882, 10.1074/jbc.M601387200 · DOI
  15. Smeitink, 2001, The genetics and pathology of oxidative phosphorylation, Nat. Rev. Genet., 2, 342, 10.1038/35072063 · DOI
  16. Stewart, 2008, Strong purifying selection in transmission of mammalian mitochondrial DNA, PLoS Biol., 6, e10, 10.1371/journal.pbio.0060010 · DOI
  17. Trifunovic, 2008, Mitochondrial dysfunction as a cause of ageing, J. Intern. Med., 263, 167, 10.1111/j.1365-2796.2007.01905.x · DOI
  18. Trifunovic, 2005, Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production, Proc. Natl. Acad. Sci. USA, 102, 17993, 10.1073/pnas.0508886102 · DOI · Paper page
  19. Ugalde, 2003, Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene, Ann. Neurol., 54, 665, 10.1002/ana.10734 · DOI
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Metadata

Authors
Edgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M. A., Nijtmans, L., Nedergaard, J., Cannon, B., Larsson, N.-G., & Trifunovic, A.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2009-08
Volume
10
Issue
2
Pages
131-138
ISSN
1550-4131
DOI
10.1016/j.cmet.2009.06.010
Cited by
195
References
3
Language
en
Licence
Funders
  • Åke Wiberg Stiftelse
  • Vetenskapsrådet

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