Mitochondrial DNA somatic mutation in cancer

Abstract

Cancer cells are known to drastically alter cellular energy metabolism. The Warburg effect has been known for over 80 years as pertaining cancer-specific aerobic glycolysis. As underlying molecular mechanisms are elucidated so that cancer cells alter the cellular energy metabolism for their advantage, the significance of the modulation of metabolic profiles is gaining attention. Now, metabolic reprogramming is becoming an emerging hallmark of cancer. Therapeutic agents that target cancer energy metabolism are under intensive investigation, but these investigations are mostly focused on the cytosolic glycolytic processes. Although mitochondrial oxidative phosphorylation is an integral part of cellular energy metabolism, until recently, it has been regarded as an auxiliary to cytosolic glycolytic processes in cancer energy metabolism. In this review, we will discuss the importance of mitochondrial respiration in the metabolic reprogramming of cancer, in addition to discussing the justification for using mitochondrial DNA somatic mutation as metabolic determinants for cancer sensitivity in glucose limitation.

Keywords: Aerobic glycolysis; Cancer; Efficacy; Mitochondrial DNA; Oncobiguanide; Oxidative phosphorylation; Somatic mutation; Toxicity; Warburg effect.

Fig. 1.. Tumor bioenergetics. (A) non-proliferating normal cells utilize glycolysis and oxidative phosphorylation to fully oxidize glucose. Most of ATP are generated through glucose oxidation. (B) In a classical view on the Warburg effect, cancer cells enhance glycolysis to compensate the reduced ATP production due to dysfunctional mitochondria. Incomplete oxidation of glucose leads to production of lactate. Causal role of dysfunctional mitochondria in the enhanced glycolysis in cancer cells is yet to be empirically confirmed. (C) In a current view on cancer energy metabolism, cancer cells generate most of ATP through mitochondrial oxidative phosphorylation. Enhanced glycolysis as well as anaplerosis/cataplerosis support anabolic metabolism of cancer cells for the rapid proliferation. (D) Targeted drugs for TAC cycle or oxidative phosphorylation lead to drastic decrease in ATP generation. Impact on the rapidly proliferating cancer cells would be more drastic than slowly growing cancer cells or non-proliferating normal cells when ATP generation is reduced. Mitochondrial DNA somatic mutations will potentiate susceptibility of cancer cells to the targeted drugs for TCA cycle or oxidative phosphorylation, whereas drug toxicity on normal cells will be reduced.