An Inherited Heteroplasmic Mutation in Mitochondrial Gene COI in a Patient with Prostate Cancer Alters Reactive Oxygen, Reactive Nitrogen and Proliferation

Rebecca S. Arnold,Douglas C. Wallace,Sean O'Hearn,Jendai C. Richards,Adeboye O. Osunkoya,John A. Petros,Carrie Q. Sun,Qian Sun

doi:10.1155/2013/239257

Abstract

Mitochondrial DNA (mtDNA) mutations have been found in many cancers but the physiological derangements caused by such mutations have remained elusive. Prostate cancer is associated with both inherited and somatic mutations in the cytochrome c oxidase (COI) gene. We present a prostate cancer patient-derived rare heteroplasmic mutation of this gene, part of mitochondrial respiratory complex IV. Functional studies indicate that this mutation leads to the simultaneous decrease in cytochrome oxidation, increase in reactive oxygen, and increased reactive nitrogen. These data suggest that mitochondrial DNA mutations resulting in increased reactive oxygen and reactive nitrogen generation may be involved in prostate cancer biology.

Highlights

E mitochondrion contains the only functional DNA outside the eukaryotic cell nucleus and mutations in this genome have been linked to a vast array of human disease including pediatric neurologic disease, degenerative muscular disease, and blindness in the pediatric population and more recently to chronic diseases of adults including diabetes, Alzheimer’s dementia, Parkinson’s disease, cardiovascular disease, and cancer [1]
Functional studies indicate that this mutation leads to the simultaneous decrease in cytochrome oxidation, increase in reactive oxygen, and increased reactive nitrogen. ese data suggest that mitochondrial DNA mutations resulting in increased reactive oxygen and reactive nitrogen generation may be involved in prostate cancer biology
We investigated the Mitochondrial DNA (mtDNA) from a patient with prostate cancer and found a heteroplasmic missense mutation in the mitochondrial c oxidase (COI) gene that impairs the oxidation of cytochrome c and increases the generation of both reactive oxygen species (ROS) and reactive nitrogen species (RNS)

Summary

Introduction

E mitochondrion contains the only functional DNA outside the eukaryotic cell nucleus and mutations in this genome have been linked to a vast array of human disease including pediatric neurologic disease, degenerative muscular disease, and blindness in the pediatric population and more recently to chronic diseases of adults including diabetes, Alzheimer’s dementia, Parkinson’s disease, cardiovascular disease, and cancer [1]. Severe mutations can exist and even be passed between generations if they exist in a state of heteroplasmy where some copies of the genome contain the mutation and some are wild type For this reason, one indication that a mitochondrial DNA (mtDNA) mutation is potentially pathogenic is that it exists in a heteroplasmic state, though this is not strictly necessary in all cases. Mutations in the mitochondrial cytochrome c oxidase subunit I (COI) gene are found at disproportionately high rates in prostate cancer patients compared to either the general population or rigorously de ned controls without prostate cancer [5]. We investigated the mtDNA from a patient with prostate cancer and found a heteroplasmic missense mutation in the mitochondrial COI gene that impairs the oxidation of cytochrome c (respiratory complex IV inhibition) and increases the generation of both reactive oxygen species (ROS) and reactive nitrogen species (RNS)

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Results

Conclusion