You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2010221 FUNCTIONAL ANALYSIS OF A RARE MUTATION OF MITOCHONDRIAL DNA FOUND IN A PROSTATE CANCER Rebecca Arnold, Adeboye Osunkoya, Sean O'Hearn, Fray Marshall, Douglas Wallace, Hong Yi, Elizabeth Wright, Carrie Sun, Les Costello, and John Petros Rebecca ArnoldRebecca Arnold Atlanta, GA More articles by this author , Adeboye OsunkoyaAdeboye Osunkoya Atlanta, GA More articles by this author , Sean O'HearnSean O'Hearn Irvine, CA More articles by this author , Fray MarshallFray Marshall Atlanta, GA More articles by this author , Douglas WallaceDouglas Wallace Irvine, CA More articles by this author , Hong YiHong Yi Atlanta, GA More articles by this author , Elizabeth WrightElizabeth Wright Atlanta, GA More articles by this author , Carrie SunCarrie Sun Atlanta, GA More articles by this author , Les CostelloLes Costello Baltimore, MD More articles by this author , and John PetrosJohn Petros Atlanta, GA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.279AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Mitochondrial DNA mutations are present in prostate cancer patients both as modulators of inherited predisposition to disease and as somatically acquired mutations in the cancer. In addition, mtDNA mutations can markedly influence metastatic capability of tumor cells in animal models. One gene in particular (cytochrome oxidase 1 [COI]) has been linked to prostate cancer (PNAS 102:719-724, 2005). We describe a rare heteroplasmic mutation of this gene in a patient with prostate cancer and the functional consequences of the mutation. METHODS We performed complete gene sequencing of the COI gene in laser capture microdissected patient prostate cancer tissue, peripheral blood and lymphoblast cell lines derived from the patient. Comparison to reference sequence and large online databases was done to ascertain the likelihood of pathogenicity. The activity of the enzyme (cytochrome oxidase) encoded by this gene was determined by dual wavelength spectrophotometry and reactive oxygen generation was determined using flow cytometric analysis of DCF-DA fluorescence. Electron microscopy of mutant and wild type prostate cancer cells was done. RESULTS The highly conserved DNA base (T) at nucleotide position 6124 of the mitochondrial genome was found to be mutated (to C) resulting in the amino acid substitution Met74Thr. This alteration resulted in a 29% decrease in activity of cytochrome oxidase (for which the COI gene constitutes the catalytic core) and a 1.75-fold increase in reactive oxygen (superoxide anion) production. The mutation was found to be heteroplasmic (existing in both mutant and wild type forms in approximately equal amounts) in the patient cancer tissue. Electron microscopy revealed substantial morphologic derangement of the mitochondria only in the presence of mutation. CONCLUSIONS A rare mutation of the mitochondrial gene previously linked to prostate cancer has been found in a patient and studied functionally and structurally in the laboratory. The mutation causes severe morphologic alteration of mitochondrial ultrastructure. The presumed link between mtDNA mutation and carcinogenesis (increased production of reactive oxygen species) has been definitively confirmed for this discrete amino acid altering mutation. The CO1 mutation induces a dysfuntional cytochrome oxidase activity resulting in an increase in ROS. These results are demonstrative of the important role of altered mitochondrial oxidative metabolism in prostate and other cancers. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byAtala A (2018) Re: Bone Metastasis in Prostate Cancer: Recurring Mitochondrial DNA Mutation Reveals Selective Pressure Exerted by the Bone MicroenvironmentJournal of Urology, VOL. 196, NO. 3, (957-958), Online publication date: 1-Sep-2016. Volume 183Issue 4SApril 2010Page: e87 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rebecca Arnold Atlanta, GA More articles by this author Adeboye Osunkoya Atlanta, GA More articles by this author Sean O'Hearn Irvine, CA More articles by this author Fray Marshall Atlanta, GA More articles by this author Douglas Wallace Irvine, CA More articles by this author Hong Yi Atlanta, GA More articles by this author Elizabeth Wright Atlanta, GA More articles by this author Carrie Sun Atlanta, GA More articles by this author Les Costello Baltimore, MD More articles by this author John Petros Atlanta, GA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...