Mitochondria as biosynthetic factories for cancer proliferation

Abstract

Unchecked growth and proliferation is a hallmark of cancer, and numerous oncogenic mutations reprogram cellular metabolism to fuel these processes. As a central metabolic organelle, mitochondria execute critical biochemical functions for the synthesis of fundamental cellular components, including fatty acids, amino acids, and nucleotides. Despite the extensive interest in the glycolytic phenotype of many cancer cells, tumors contain fully functional mitochondria that support proliferation and survival. Furthermore, tumor cells commonly increase flux through one or more mitochondrial pathways, and pharmacological inhibition of mitochondrial metabolism is emerging as a potential therapeutic strategy in some cancers. Here, we review the biosynthetic roles of mitochondrial metabolism in tumors and highlight specific cancers where these processes are activated.

Keywords: Amino acids; Anaplerosis; Biosynthesis; Cancer; Lipogenesis; Mitochondria; Nucleotides.

Figure 1

Biosynthetic nodes within mitochondria. Metabolic pathways within mitochondria that contribute to biosynthesis in cancer and other proliferating cells. TCA metabolism and FOCM enable cells to convert carbohydrates and amino acids to lipids, non-essential amino acids, nucleotides (including purines used for cofactor synthesis), glutathione, heme, and other cellular components. Critical biosynthetic routes are indicated by yellow arrows. Enzymatic reactions that are dependent on redox-sensitive cofactors are depicted in red.

Figure 2

Coordination of carbon and nitrogen metabolism across amino acids. Glutamate and aKG are key substrates in numerous transamination reactions and can also serve as precursors for glutamine, proline, and the TCA cycle. Mitochondrial enzymes catalyzing these reactions are highlighted in blue, and TCA cycle intermediates are highlighted in orange (pyruvate enters the TCA cycle as acetyl-CoA or oxaloacetate).

Figure 3

Biosynthetic sources for purine and pyrimidine synthesis. Sources and fates of nitrogen, carbon, and oxygen atoms are colored as indicated. Italicized metabolites can be sourced from the mitochondria or cytosol. The double bond formed by the action of DHODH/ubiquinone is also indicated.