Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers

Abstract

Mitochondria are key organelles in eukaryotic cells principally responsible for multiple cellular functions. In addition to a plethora of somatic mutations as well as polymorphic sequence variations in mitochondrial DNA (mtDNA), the identification of increased or reduced mtDNA copy number has been increasingly reported in a broad range of primary human cancers, underscoring that accumulation of mtDNA content alterations may be a pivotal factor in eliciting persistent mitochondrial deficient activities and eventually contributing to cancer pathogenesis and progression. However, the detailed roles of altered mtDNA amount in driving the tumorigenic process remain largely unknown. This review outlines mtDNA content changes present in various types of common human malignancies and briefly describes the possible causes and their potential connections to the carcinogenic process. The present state of our knowledge regarding how altered mtDNA quantitative levels could be utilized as a diagnostic biomarker for identifying genetically predisposed population that should undergo intensive screening and early surveillance program is also discussed. Taken together, these findings strongly indicate that mtDNA copy number alterations may exert a crucial role in the pathogenic mechanisms of tumor development. Continued insights into the functional significance of altered mtDNA quantities in the etiology of human cancers will hopefully help in establishing novel potential targets for anti-tumor drugs and intervention therapies.

Introduction

Mitochondria are cytoplasmic organelles of the eukaryotic system that exert essential functions in energy metabolism, free radical production, calcium homeostasis and apoptosis (Wallace, 2010). Although a majority of proteins participating in the electron transport system are synthesized by nuclear DNA (nDNA) and then imported into the mitochondrial compartment, mitochondria possess their own genome, namely mitochondrial DNA (mtDNA), which exists at hundreds to thousands of copies per mammalian cell and varies widely in number with cell or tissue origin (Clay Montier et al., 2009). The content of mtDNA is precisely modulated according to cellular physiological conditions and may undergo significant changes under diverse internal or external microenvironments, such as hypoxia and steroid hormone stimulation (Hoppeler et al., 2003, Shadel, 2008, Weitzel et al., 2003). Human mtDNA is a 16569 bp, maternally inherited, closed circular double-stranded molecule encoding 13 core polypeptide subunits of the respiratory chain apparatus, two rRNAs and a set of 22 tRNAs required for mitochondrial protein synthesis (Chen and Butow, 2005). In addition to the coding sequences, mtDNA contains a unique 1124 bp noncoding fragment at nucleotide positions 16024-576, designated as the displacement (D)-loop, which serves as a major regulatory site responsible for controlling mtDNA replication and transcription (Clayton, 2000). Since mtDNA duplication is not synchronized with nDNA, mtDNA may independently replicate more than once during each cell cycle, even in non-dividing cells. By virtue of the absence of protective histones, limited DNA repair capacity, lack of introns and its close physical proximity to high levels of endogenous reactive oxygen species (ROS) in the mitochondrial inner membrane, mtDNA is extremely prone to oxidative or other genotoxic damages and thus acquire mutations at a much higher rate (10- to 200-fold) than nDNA (Liu and Demple, 2010).

Mitochondrial functional defects have long been hypothesized to contribute to the development and probably progression of cancer. Given the central role of mtDNA in maintaining normal mitochondrial function, considerable efforts have been devoted over the past two decades to better define the potential implication of mtDNA copy number aberrations in the carcinogenic process. Besides a heavy load of somatic mutations including point mutations, large-scale deletions and insertions accumulated in both the coding and control regions of mtDNA, quantitative changes in mtDNA have been frequently identified in various types of solid tumors as well as in hematologic malignancies, such as leukemias and lymphoma (Lee and Wei, 2009, Lu et al., 2009). In this review, I first summarize the published spectra of mtDNA copy number changes observed in common primary human neoplasms. Next, this review attempts to highlight recent advances in our understanding of the causal roles of quantitative mtDNA variations in neoplastic transformation and tumor progression. The potential clinical application of altered mtDNA levels as a novel predictive and diagnostic biomarker is also addressed.