A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors

Abstract

Since Otto Warburg made the first observation that tumor cells exhibit altered metabolism and bioenergetics in the 1920s, many scientists have tried to further the understanding of tumor bioenergetics. Particularly, in the past decade, the application of the state-of the-art metabolomics and genomics technologies has revealed the remarkable plasticity of tumor metabolism and bioenergetics. Firstly, a wide array of tumor cells have been shown to be able to use not only glucose, but also glutamine for generating cellular energy, reducing power, and metabolic building blocks for biosynthesis. Secondly, many types of cancer cells generate most of their cellular energy via mitochondrial respiration and oxidative phosphorylation. Glutamine is the preferred substrate for oxidative phosphorylation in tumor cells. Thirdly, tumor cells exhibit remarkable versatility in using bioenergetics substrates. Notably, tumor cells can use metabolic substrates donated by stromal cells for cellular energy generation via oxidative phosphorylation. Further, it has been shown that mitochondrial transfer is a critical mechanism for tumor cells with defective mitochondria to restore oxidative phosphorylation. The restoration is necessary for tumor cells to gain tumorigenic and metastatic potential. It is also worth noting that heme is essential for the biogenesis and proper functioning of mitochondrial respiratory chain complexes. Hence, it is not surprising that recent experimental data showed that heme flux and function are elevated in non-small cell lung cancer (NSCLC) cells and that elevated heme function promotes intensified oxygen consumption, thereby fueling tumor cell proliferation and function. Finally, emerging evidence increasingly suggests that clonal evolution and tumor genetic heterogeneity contribute to bioenergetic versatility of tumor cells, as well as tumor recurrence and drug resistance. Although mutations are found only in several metabolic enzymes in tumors, diverse mutations in signaling pathways and networks can cause changes in the expression and activity of metabolic enzymes, which likely enable tumor cells to gain their bioenergetic versatility. A better understanding of tumor bioenergetics should provide a more holistic approach to investigate cancer biology and therapeutics. This review therefore attempts to comprehensively consider and summarize the experimental data supporting our latest view of cancer bioenergetics.

Keywords: Glutamine; Heme; Hemoprotein; Metabolic mutations; Mitochondrial respiration; Mitochondrial transfer; Oxidative phosphorylation; Tumor bioenergetics; Tumor heterogeneity.

Fig. 1

The metabolic steps of glycolysis and TCA cycle. The steps involved in glycolysis and TCA cycle are demarcated separately. ATP/GTP utilization or synthesis is shown in green, while NAD⁺/NADH and FAD/FADH₂ are shown in red. Also indicated are the numbers of NADH, FADH₂, and ATP/GTP generated when one molecule of glucose is consumed following glycolysis, TCA cycle, and oxidative phosphorylation. Abbreviations: Glucose-6-P glucose 6-phosphate, Fructose-6-P fructose 6-phosphate, Fructose -1,6-bis-P fructose 1,6-bisphosphate, Dihydroxyacetone-P dihydroxyacetone phosphate, Glyceraldehyde-3-P glyceraldehyde 3-phosphate, 1,3-Bis-P-glycerate 1,3-bisphosphoglycerate, 3-P-Glycerate 3-phosphoglycerate, 2-P-Glycerate 2-phosphoglycerate, OXPHOS oxidative phosphorylation

Fig. 2

Metabolic fuels for tumor cells. Tumor cells are able to use a variety of bioenergetic substrates, including glutamine, glucose, fatty acids (FA), ketone bodies, and acetate (highlighted by red boxes). These substrates can be provided by stromal cells in the microenvironment. Much of the cellular energy for tumor cells is likely generated by TCA cycle coupled to oxidative phosphorylation. The pathways for the generation and metabolism of these substrates are outlined. Notably, glutamine and glucose can also provide building blocks for the synthesis of many biomolecules. Also indicated in pink are the metabolic enzymes whose mutations are found in various tumors and the accumulated oncometabolites in these tumors

Fig. 3

The function and composition of mitochondrial OXPHOS complexes I–V. Shown here are the directions of electron and proton transport by the OXPHOS complexes. Also indicated are the origins of DNA encoding the subunits and the hemes needed for complexes II–IV. nDNA nuclear DNA, mtDNA mitochondrial DNA

Fig. 4

The signaling and structural functions of heme in human cells. Human cells can synthesize heme de novo in mitochondria (the first and rate-limiting enzyme is ALAS, 5-aminolevulinate synthase) or import heme via heme transporters, such as HRG1 and HCP1. Inside cells, heme serves as a prosthetic group in numerous enzymes and proteins that transport, store, or use oxygen, such as mitochondrial cytochromes and cytochrome P450. Additionally, heme directly regulates the activity of diverse cellular signaling and regulatory molecules, such as Bach1, Rev-ERBα, and Rev-ERBβ (transcriptional regulators), as well as DGCR8 (an essential miRNA processing factor) in the nucleus. Heme also regulates HRI (the heme-regulated inhibitor kinase controlling protein synthesis) and the Ras-ERK signaling pathway in the cytoplasm. Furthermore, heme regulates the activity of the NMDA receptor, the SloBK potassium channel, and the ENaCs sodium channel on the cell membrane