Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.

W T Y Lee,J Johnson,T G Johns,J C St John,A Cuddihy,J E Cain,K-Y Yeung,A Dickinson,D N Watkins,B Kumar,A Spencer

doi:10.1038/cddiscovery.2016.16

Abstract

Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.

Highlights

The human mitochondrial genome is 16.6 kb in size, circular and encodes 13 key genes of the electron transfer chain (ETC), which generates the vast majority of cellular ATP through the process of oxidative phosphorylation (OXPHOS).[1]
We have used three independent experimental models consisting of glioblastoma multiforme (GBM), a primary brain tumour that is neural in origin and a solid tumour;[5] multiple myeloma (MM), a haematological tumour that originates from terminally differentiated B cells;[6] and osteosarcoma, a solid tumour originating from osteoblast precursors.[7]
To determine whether haematological tumours are dependent on mtDNA for tumorigenesis, we depleted human MM U266 cells labelled with luciferase to 10% (U26610), 0.12% (U2660.12), 0.05% (U2660.05) and 0.04% (U2660.04) of their original mtDNA content (U266100; Figure 1a) and transplanted them and non-depleted (U266100) cells into immunocompromised mice

Summary

Introduction

The human mitochondrial genome (mtDNA) is 16.6 kb in size, circular and encodes 13 key genes of the electron transfer chain (ETC), which generates the vast majority of cellular ATP through the process of oxidative phosphorylation (OXPHOS).[1]. Disruption of the ETC due to mutation, deletion or depletion of mtDNA is associated with an increasing number of diseases.[2] mtDNA copy number and variants have been associated with cancer,[3,4] it remains to be determined whether the regulation of mtDNA copy number and the ability of mtDNA to acquire de novo variants are instrumental in driving tumorigenesis and, if so, how they affect the tumour phenotype. MtDNA copy number and variants are modulated at different stages of tumorigenesis. Altering a tumour cell’s mtDNA content results in changes to nuclear gene expression that directly affect the severity of the tumour phenotype

Methods

Results

Conclusion