Mitochondrial DNA mutations in ageing and cancer

Abstract

Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age-related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.

Keywords: ageing; cancer; metabolism; mitochondria; mitochondrial DNA; oxidative phosphorylation.

Fig. 1

The human mitochondrial genome. The outer circle depicts the heavy strand with the inner circle representing the light strand. Genes encoding proteins of the mitochondrial respiratory chain are shown as coloured blocks labelled accordingly (MT‐ND1–6, MT‐COI–III, MT‐ATP6 and 8 and MT‐CYB). The blue blocks denote the two ribosomal RNA and red dashes represent each of the 22 tRNA. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 2

Clonal expansion of mtDNA mutations through mitotic segregation. Somatic mitochondrial DNA (mtDNA) mutations occur randomly primarily through replication errors, as well as mis‐incorporation of incorrect bases opposite oxidative adducts. Upon cell division, mtDNA molecules randomly segregate to daughter cells and are then replicated to maintain consistent mtDNA copy number. This could either result in loss of the mutation or clonal expansion within that cell lineage. Through multiple successive rounds of cell division and vegetative segregation, the mutated mtDNA molecules can become the dominant species within the cell. When the critical threshold for mutated mtDNA is reached, the wild‐type molecules are no longer able to compensate and a biochemical defect in oxidative phosphorylation (OXPHOS) occurs. A schematic of the colonic epithelium is shown here, and brown crypts represent those with low‐level mtDNA mutations and normal OXPHOS activity. The blue crypt represents a crypt in which the mtDNA mutation load has crossed the threshold and has a measurable OXPHOS deficiency. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 3

Hypothesized mechanisms by which mtDNA mutations may contribute to tumorigenesis. Three proposed mechanisms by which mitochondrial DNA (mtDNA) mutations may contribute to tumourigenesis. (1) mtDNA mutations can induce tumourigenesis directly followed by mutations to the nuclear genome as has been shown for renal oncocytomas. (2) mtDNA mutations occur and clonally expand over time until a biochemical oxidative phosphorylation (OXPHOS) defect and metabolic rewiring occur. Following oncogenic transformation through nuclear DNA mutations, mtDNA mutations may (i) provide a favourable metabolic environment for growth, provide resistance to therapy or enhance metastatic potential, (ii) be neutral and have no effect on tumourigenesis and (iii) not be compatible with tumourigenesis and cause cell death. (3) Low‐level mtDNA mutations which occur before or after transformation can clonally expand very rapidly due to the high rates of cell division within the tumour. mtDNA mutations with favourable effects on tumourigenesis could cause clonal evolution of that lineage, whereas lineages containing mtDNA mutations that do not confer a favourable phenotype could become extinct. [Colour figure can be viewed at wileyonlinelibrary.com]