Quantitative proteomic analysis of mitochondrial proteins reveals prosurvival mechanisms in the perpetuation of radiation-induced genomic instability

Stefani N. Thomas, Katrina M. Waters, William F. Morgan, Austin J. Yang, Janet E. Baulch

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13 Scopus citations


Radiation-induced genomic instability is a well-studied phenomenon that is measured as mitotically heritable genetic alterations observed in the progeny of an irradiated cell. The mechanisms that perpetuate this instability are unclear; however, a role for chronic oxidative stress has consistently been demonstrated. In the chromosomally unstable LS12 cell line, oxidative stress and genomic instability were correlated with mitochondrial dysfunction. To clarify this mitochondrial dysfunction and gain insight into the mechanisms underlying radiation-induced genomic instability we have evaluated the mitochondrial subproteome and performed quantitative mass spectrometry analysis of LS12 cells. Of 98 quantified mitochondrial proteins, 17 met criteria for fold changes and reproducibility; and 11 were statistically significant in comparison with the stable parental GM10115 cell line. Previous observations implicated defects in the electron transport chain (ETC) in the LS12 cell mitochondrial dysfunction. Proteomic analysis supports these observations, demonstrating significantly reduced levels of mitochondrial cytochrome c, the intermediary between complexes III and IV of the ETC. Results also suggest that LS12 cells compensate for ETC dysfunction and oxidative stress through increased levels of tricarboxylic acid cycle enzymes and upregulation of proteins that protect against oxidative stress and apoptosis. More than one cellular defect is likely to contribute to the genomic instability phenotype, and evaluation of gene and microRNA expression suggests that epigenetics play a role in the phenotype. These data suggest that LS12 cells have adapted mechanisms that allow survival under suboptimal conditions of oxidative stress and compromised mitochondrial function to perpetuate genomic instability.

Original languageEnglish (US)
Pages (from-to)618-628
Number of pages11
JournalFree Radical Biology and Medicine
Issue number3
StatePublished - Aug 1 2012
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to Dr. Umut Aypar for his scientific and intellectual input. This work was supported by Department of Energy Low Dose Program Glue Grant DE-FG02-07ER64339 (W.F.M./J.E.B.), NASA Grant NNX07AT42G (J.E.B.), NIH R01AG25323 (A.J.Y.), and NIH P30CA134274 (Greenebaum Cancer Center Support Grant) as well as by Battelle Memorial Institute, Pacific Northwest Division, under Contract DE-AC05-76RL0 1830 with the U.S. Department of Energy, Office of Biological and Environmental Research Low Dose Science Program. The U.S. Government retains and the publisher, by accepting the article for publication, acknowledges that the U.S. Government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this article, or allow others to do so, for U.S. Government purposes.


  • Epigenetics
  • Free radicals
  • Genomic instability
  • Mitochondria
  • Proteomics
  • Quantitative mass spectrometry
  • miR


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