Mitochondrial defects in cancer

Abstract

Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Defects in mitochondrial function have long been suspected to contribute to the development and progression of cancer. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in various types of cancer, and offer some perspective as to the emergence of mtDNA mutations, their functional consequences in cancer development, and therapeutic implications.

Figure 1

The mitochondrial electron transport chain complexes are encoded by two genetic systems: the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA). The mtDNA codes for 7 NADH dehydrogenase (ND) subunits for complex I, a cytochrome b for complex III, 3 cytochrome c oxidase (COX) subunits for complex IV, and 2 ATPase (ATPase6/8) for complex V. Complex II is solely encoded by nDNA. The solid arrows indicate the direction of electron flow in the respiration chain; dashed arrows indicate the flow of genetic information from mtDNA or nDNA to RNA to protein; the numbers indicate the actual number of protein subunits coded by each genetic system. Specific inhibitors of RNA transcription or protein translation with relative selectivity for each genetic system are indicated in blue.

Figure 2

Schematic illustration of somatic mtDNA mutation. Mitochondrial DNA mutations can be induced by endogenous or exogenous DNA-damaging agents such as ROS, chemical agents, and radiation. The numbered arrows indicate possible outcomes of mtDNA mutations including heteroplasmic and homoplasmic states. See text for detail.