An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Abstract

Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD⁺/NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.

Keywords: cancer; mitochondria; tumor metabolism; tumor metastasis.

Figure 1

The OXPHOS pathway. Mitochondria produce ATP via OXPHOS carried out by ETC and synthase. In humans, the OXPHOS is comprised of five complexed embedded in the inner mitochondria membrane (IMM), the ETC (complex I-IV) are responsible for the transfer of electrons from NADH and FADH2 to oxygen which is the final electron acceptor. This electron transportation generates the electrochemical gradient across the IMM. The proton gradient drives the translocation of protons from intermembrane space back into the matrix via the ATP synthase (Complex V (CV)) that catalyzes the conversion of ADP to ATP.

Figure 2

Mitochondria in ATP, lipid, and nucleic acid metabolism. Glycolysis regulated by PFK1 produces pyruvate and NADH from glucose and then the pyruvate enters the mitochondria under aerobic conditions and fuels the TCA cycle which produces produce metabolites. Mitochondria generate ATP through OXPHOS mainly by using pyruvate derived from glycolysis. In the absence of glucose, ATP will be produced via the degradation of fatty acids and proteins. Ketone bodies will be produced from FAO when the glucose is insufficient. Ketone bodies are generated in the mitochondrial matrix of liver cells and are subsequently exported via the blood to other organs to cover the energy demands. When the glucose transporters or ETC complexes deficiency happens, the glucose metabolism and the oxidation of pyruvate in mitochondria are bypassed, and cellular energy supply will be shifted from glucose to ketone bodies. Fatty acids are transferred from the cytosol to mitochondria by SLC25A20. In the TCA cycle, oxaloacetate generated from malic acid is transaminated to aspartate under the catalysis of transaminase and aspartate is the intermediate for synthesizing both purine and pyrimidine bases. Small metabolites or molecules are transported to the matrix of mitochondria by MCFs, which transport ADP into the mitochondrial matrix for ATP synthesis and ATP out to reach high cytosolic ATP concentrations for energy-requiring reactions.

Figure 3

Mitochondria function in cancer metabolism. 1) Mutation of enzymes in TCA cycles such as mutation of IDH, SDH leads to high concentrations of D2HG, fumarate and succinate accumulation promoting tumor cell proliferation and progression. These enzymes also serve as the driver of human cancer. The metabolic dysregulation is not only a consequence of oncogenic transformation but also that it drives cancer. 2) Acetyl-CoA which is the most important substrates for acetylation modification, can be derived from glucose (pyruvate oxidation), fatty acid, and amino acid catabolism, it is the key indicator of cell metabolism and links metabolism, signaling, and epigenetics. 3) Succinate exists intracellular (cytosol and mitochondria) and extracellular, its efflux from mitochondria to the cytosol relies on SLC25 and VDAC.

Figure 4

Differences of mitochondrial functions in cancer stem cell and bulk cancer cell. Cancer stem cells acquire their energy more from OXPHOS. High expression of PGC-1α enhances mitochondrial biogenesis, strong antioxidant activity and fewer ROS, increases OXPHOS and promotes cancer cells' invasion and metastasis. CSCs possess a more powerful antioxidant defense system which can counteract and scavenge ROS to keep their low ROS level and maintain their stemness and tumorigenesis. Mitophagy is essential in the differentiation and in the acquisition of “stemness” in cancer stem cells, it promotes CSC plasticity for better adaption in TME. CSCs have inactive mPTP and bulk tumor cells have active mPTP .