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.

Cancer metabolism in space and time: Beyond the Warburg effect

“…In vivo, can cer cells are grow ing close to sur round ing stro mal cells and may re pro gram their me tab o lism at their ad van tage. Un der the ac tion of in flam ma tory cy tokines, stro mal cells and adipocytes re lease meta bolic fu els for can cer cells [249][250][251]. In this chap ter, we will pro vide ad di tional ex am ples show ing that the 3D ar chi tec ture, the tu mor en vi ron ment and the tis sue of ori gin are other ma jor dri vers of tu mor me tab o lism.…”

The Bioenergetic Role of Mitochondria in Lung Cancer

“…Intensified oxygen consumption allows increased cancer cell proliferation and function [17]. Recent research suggests that non-small cell lung cancer (NSCLC) cells upregulate proteins that stimulate heme synthesis, uptake, and function.…”

“…Thus, no methods are currently available to effectively treat these patients. However, several recent experiments strongly suggest that targeting mitochondria will yield effective strategies to treat lung cancer patients in the future [14][15][16][17][18].…”

A review on the cell biology and toxicology within the correlation to a new achievement

“…Therefore, a level of toxicology subspecialties have been developed and will be lately defined within the development of biotechnologies and the latent understanding of toxicogenomics and ecotoxicology or aquatic, chemical, clinical, environmental, forensic, medical, occupational, and regulatory toxicology. According to that, future issues of the journal will concentrate on both the clinical and translational work through an emphasis on the molecular in a cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular addition to the merger of cell biology and toxicology that enables a deeper insight of human regulation, cell type-specific function, and system biomedicine in drug discovery and development (1,2). It is well known and accepted that "adverse effects" or "toxic impacts" of elements from extracellular, intercellular, or intracellular resources contribute to the pathogeneses and exacerbations of diseases.…”