Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Proteomic analysis of cancer-cell mitochondria

Abstract

Mitochondrial dysfunction and mutations in mitochondrial DNA have been frequently reported in cancer cells. Mitochondrial gene-expression signatures of transformed cells have been identified; however, the phenotypic effects of these genetic alterations remain to be established. Identification of mitochondrial proteins that are aberrantly expressed in cancer cells has been made possible by the recent development of mitochondrial functional proteomics and could identify new markers for early detection and risk assessment, as well as targets for therapeutic intervention.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mitochondrial functions.
Figure 2: Schematic representation of mitochondrial mass spectrometry.

Similar content being viewed by others

References

  1. Fliss, M. S. et al. Facile detection of mitochondrial mutations in tumours and body fluids. Science 287, 2017–2019 (2000).

    Article  CAS  Google Scholar 

  2. Costantini, P., Jacotot, E., Decaudin, D. & Kroemer, G. Mitochondrion as a novel target of anticancer chemotherapy. J. Natl Cancer Inst. 92, 1042–1053 (2000).

    Article  CAS  Google Scholar 

  3. Kroegmer, G. Mitochondrial control of aopotosis. Biochem. Soc. Symp. 66, 1–15 (1999).

    Article  Google Scholar 

  4. Thress, K., Kornbluth, S. & Smith, J. J. Mitochondria at the crossroad of apoptotic cell death. Mitochondria at the crossroad of apoptotic cell death. J. Bioenerg. Biomembr. 31, 321–326 (1999).

    Article  CAS  Google Scholar 

  5. Fernandez, M. G. et al. Early changes in intramitochondrial cardiolipin distribution during apoptosis. Cell Growth Differ. 13, 449–455 (2002).

    CAS  Google Scholar 

  6. Alonso, A. et al. Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis. Electrophoresis 18, 682–685 (1997).

    Article  CAS  Google Scholar 

  7. Anderson, L. & Seilamer, J. A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 18, 533–537 (1997).

    Article  CAS  Google Scholar 

  8. Jeronimo, C. et al. Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene 20, 5195–5198 (2001).

    Article  CAS  Google Scholar 

  9. Jones, J. B. et al. Detection of mitochondrial DNA mutations in pancreatic cancer offers a 'mass'-ive advantage over detection of nuclear DNA mutations. Cancer Res. 61, 1299–1304 (2001).

    CAS  Google Scholar 

  10. Copeland, W., Waschman, J., Johnson, J. & Penta, J. Mitochondrial DNA alterations in cancer. Cancer Invest. 20, 557–569 (2002).

    Article  CAS  Google Scholar 

  11. Ha, P. K. et al. Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation. Clin. Cancer Res. 8, 2260–2265 (2002).

    CAS  Google Scholar 

  12. Sanchez–Cespedes et al. Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res. 61, 7015–7019 (2001).

    Google Scholar 

  13. Parrella, P. et al. Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res. 61, 7623–7626 (2001).

    CAS  Google Scholar 

  14. Nomoto, S., Yamashita, K., Koshikawa, K., Nakao, A. & Sidransky, D. Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasma. Clin. Cancer Res. 8, 481–487 (2002).

    CAS  Google Scholar 

  15. Eng, C. Kiuru, M., Fernandez, M. J. & Aaltonen, L. A. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nature Rev. Cancer 3, 193–202 (2003).

    Article  CAS  Google Scholar 

  16. Lopez, M. F. & Melov, S. Applied proteomics: mitochondrial proteins and effect on function. Circ. Res. 90, 380–389 (2002)

    Article  CAS  Google Scholar 

  17. Tan, D. J. et al. Novel heteroplasmic frameshift and missense somatic mitochondrial DNA mutations in oral cancer of betel quid chewers. Genes Chromosom. Cancer 37, 186–194 (2003).

    Article  CAS  Google Scholar 

  18. Murray, J., Gilkerson, R. & Capaldi, R. A. Quantitative proteomics: the copy number of pyruvate dehydrogenase is more than 102 fold lower than that of complex III in human mitochondria. FEBS Lett. 529, 173–178 (2002).

    Article  CAS  Google Scholar 

  19. Petricoin, E. F. & Liotta, L. A. Mass spectrometry based diagnostics: the upcoming revolution in disease detection. Clin. Chem. 49, 533–534 (2003).

    Article  CAS  Google Scholar 

  20. Vissers, J. P., Blackburn, R. K., & Moseley, M. A. A novel interface for variable nanoscale LC/MS for improved proteome coverage. J. Am. Soc. Mass Spectrom. 13, 760–771 (2002).

    Article  CAS  Google Scholar 

  21. Brookes, P. S. et al. High-throughput two-dimensional blue-native electrophoresis: a tool for functional proteomics of mitochondria and signaling complexes. Proteomics 2, 969–977 (2002).

    Article  CAS  Google Scholar 

  22. Tryoen-Toth P. et al. Proteomic consequences of a human mitochondrial tRNA mutation beyond the frame of mitochondrial translation. J. Biol. Chem. 278, 24314–24323 (2003).

    Article  CAS  Google Scholar 

  23. Anderson, N. L. & Anderson, N. G. Proteome and proteomics: new technologies, new concepts and new words. Electrophoresis 19, 1853–1861 (1998).

    Article  CAS  Google Scholar 

  24. Gygi, S. P., Rochon, Y., Franza, B. B. & Aebersold, R. Correlation between protein and mRNA abundance in yeast. Mol. Cell Biol. 19, 1720–1730 (1999).

    Article  CAS  Google Scholar 

  25. Zhou, G. et al. 2D Differential in-gel electrophoresis for the identification of esophageal scans cell cancer-specific protein markers. Mol. Cell. Proteomics 1, 117–123 (2002).

    Article  CAS  Google Scholar 

  26. Wall, D. B. et al. Three-dimensional protein map according to pI, hydophobicity and molecular mass. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 774, 53–58 (2002).

    Article  CAS  Google Scholar 

  27. Merchant, M. & Weinberger, S. R. Recent advancements in surface-enhanced laser desorption/ionization-time of flight-mass spectrometry. Electrophoresis 21, 1164–1177 (2000).

    Article  CAS  Google Scholar 

  28. Fung, E. T. & Enderwick, C. ProteinChip clinical proteomics: computational challenges and solutions. Biotechniques 34, 40–41 (2002).

    Google Scholar 

  29. Lin, T. K. et al. Specific modification of mitochondrial protein thiols in response to oxidative stress: a proteomics approach. J. Biol. Chem. 277, 17048–17056 (2002).

    Article  CAS  Google Scholar 

  30. Yu, W. et al. RRR-α-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. Cancer Res. 63, 2483–2491 (2003).

    CAS  Google Scholar 

  31. Lopez, M. F. et al. High-throughput profiling of the mitochondrial proteome using affinity fractionation and automation. Electrophoresis 21, 3427–3440 (2000).

    Article  CAS  Google Scholar 

  32. Rabilloud, T. et al. Two-dimensional electrophoresis of human placental mitochondria and protein identification by mass spectrometry: toward a human mitochondrial proteome. Electrophoresis 19, 1006–1014 (1998).

    Article  CAS  Google Scholar 

  33. Sidransky, D. Emerging molecular markers of cancer. Nature Rev. Cancer 2, 210–219 (2002).

    Article  CAS  Google Scholar 

  34. Wallace, D. C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).

    Article  CAS  Google Scholar 

  35. Tong, B. C. et al. Mitochondrial DNA alterations in thyroid cancer. J. Surg. Oncol. 82, 170–173 (2003).

    Article  CAS  Google Scholar 

  36. Mambo, E. et al. Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations. Proc. Natl Acad. Sci. USA 100, 1838–1843 (2003).

    Article  CAS  Google Scholar 

  37. Hirano, M. et al. Defects of intergenomic communication: autosomal disorders that cause multiple deletions and depletion of mitochondrial DNA. Semin. Cell Dev. Biol. 12, 417–427 (2001).

    Article  CAS  Google Scholar 

  38. Kaukonen, J. et al. A third locus predisposing to multiple deletions of mtDNA in autosomal dominant progressive external ophthalmoplegia. Am. J. Hum. Genet. 65, 256–261 (1999).

    Article  CAS  Google Scholar 

  39. Mitsumoto, A., Takeuchi, A., Okawa, K. & Nakagawa, Y. A subset of newly synthesized polypeptides in mitochondria from human endothelial cells exposed to hydroperoxide stress. Free Radic. Biol. Med. 32, 22–37 (2002).

    Article  CAS  Google Scholar 

  40. Scheffler, I. E. Mitochondria make a come back. Adv. Drug. Deliv. Rev. 49, 3–26 (2001).

    Article  CAS  Google Scholar 

  41. Rabilloud, T. et al. The mitochondrial antioxidant defence system and its response to oxidative stress. Proteomics 1, 1105–1110 (2001).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sudhir Srivastava.

Related links

Related links

DATABASES

Cancer.gov

breast cancer

colorectal cancer

gastric cancer

head and neck cancer

liver cancer

lung cancer

ovarian cancer

prostate cancer

LocusLink

apoptosis-inducing factor

BAK

BAX

BCL2

cytochrome b

cytochrome c

MTND1

MTND4

MTND5

FURTHER INFORMATION

Cancer screening

Human Proteome Organisation

Early Detection Research Network

Mitochondrial proteome database

Mitomap (genomic)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verma, M., Kagan, J., Sidransky, D. et al. Proteomic analysis of cancer-cell mitochondria. Nat Rev Cancer 3, 789–795 (2003). https://doi.org/10.1038/nrc1192

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1192

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing