mtDNA mutagenesis is involved in a wide arrange of tumor processes, including renal adenocarcinoma, colon cancer, head and neck tumors, astrocytic tumors, thyroid tumors, breast tumors, ovarian, prostate and bladder cancer tumors, neuroblastomas, and oncocytomas. Many mtDNA mutations in cancer cells clearly inhibit oxidative phosphorylation. Although some of these cancers have ancestral polymorphisms associations, others may be cancer cell mutations. ^3-6 (table 1).

Table 1

Source: Own elaboration based on the data obtained in the study.

Cancer cells acquire enough ATP to support proliferation and to function endlessly, which has captivated scientists for nearly a century. Otto Warburg et al. conducted the first quantitative study on cancer cell metabolism in the 1920s. ^7,8

Cells can obtain energy through a process called glycolysis that consists of anaerobic fermentation, in which the waste products of that fermentative process are pyruvate and lactic acid. ^9,10 Tumor tissues metabolize approximately ten times more glucose into lactate at a given time than normal tissues. ^6,8 Warburg hypothesized that effective cellular respiration caused by mitochondrial damage leads to carcinogenesis. ^9,10

Warburg’s effect describes that cancer cells use glycolysis followed by lactic fermentation as an energy source, even if there is an appropriate amount of oxygen for respiration. ^1,11 In other words, instead of developing a complete respiration process in the presence of adequate amounts of oxygen, cancer cells ferment and continue to mutate to preserve their tumoral domain. ¹²

At the cellular level, tumors have survival advantages due to lactate secretion. ^4,13,14 Lactic acid confers invasive properties to tumor cells, affecting the normal structure of tissues. ¹⁵ Additionally, the expression of vascular endothelial growth factor and its receptor (VEGF and VEGFR, respectively) responds to different stimuli to generate new blood vessels from preexisting ones. ^1,16-18 VEGFα stimulates vascular endothelial cell growth, cell survival and proliferation regulated by the nuclear and mitochondrial action of the cell. Furthermore, VEGF and gene mutations leading to actívate metalloproteinases to degrade the extracellular matrix allow greater metastatic action. ¹⁹ Recent studies suggest that VEGF can protect cells from apoptosis and increase their resistance to conventional chemotherapy and radiotherapy. ^20,21

Similarly, metastasis is of great importance since most of cáncer deaths occur because primary cancer spreads to distant sites. In most cases, cancer patients with localized tumors have a better survival rate than patients with cancer and metastatic tumors. ^22-25 It is also suggested that the increase of oncogene mutations, tumor suppressor genes and enzymes of the glycolytic pathway and/or mitocondrial oxidative metabolism (Myc, Akt, p53, HIF1-α) allow to turn cáncer cells into efficient metastatic cells. ³

The hypoxia-inducible factor (HIF-1) protein is normally activated in response to certain cellular crises, such as lack of oxygen. However, in the case of mitochondria with abnormal and tumor mechanisms, the expression of HIF-1 that is perpetuated in the presence of damage signs in the SDH gene is stimulated. This is caused by the cell following already established oncogenes guidelines to carry out a unique type of homeostasis for cancer and to supply high levels of glucose and oxygen to replicate itself without control. ^1,26,27

A wide variety of metabolic fuels can be observed in tumor pathways, in which tumor cells are able to utilize different bioenergetic substrates, including glutamine, glucose, fatty acids, ketone bodies, and acetate. These substrates can be provided by the stromal cells in the microenvironment. ²⁸ Particularly, glutamine and glucose can provide building blocks for the synthesis of many biomolecules that allow the regulation of oncogenesis processes. It is worth mentioning that metabolic enzymes with mutations are found in several tumors and in the oncometabolites accumulated in different types of tumors. ^28,29

Cancer cells also show increased demand for fatty acids other tan glutamine. ^6,30 Fatty acids can be synthesized endogenously or taken from exogenous sources. For example, prostate tumors import less glucose than other tumors, ³¹ therefore, β-oxidation of fatty acids is an important source of energy. ^32,33

Moreover, two recent studies showed that acetate is a bioenergetic substrate for glioblastoma and brain metastases. ³⁴ Catabolism in stromal and adipocyte cells provides fuel and building blocks for the anabolic growth of cancer cells through metabolic coupling. ³⁵

In 2000 and 2011, Hanahan and Weinberg summarized an extensive research on cancer and the top 10 characteristics of cancer and its correlation with mitochondria (table 2). ^36-39 These authors describe how cancer cells can be stimulated by infectious phenomena, inflammation, viruses, toxic substances and other actions that allow the proliferation of anomalous cells.

Table 2

Source: Own elaboration based on ²³.

In these works, they emphasize that the centralist vision of cáncer has transcended the anomalous production of cellular mutations, and also consider that tumor evolution is based on the appearance of changes and the stress in the cellular ecosystem that induces the genome to instability and produces mutations, signal activations with erroneous sequences and mechanisms of evasion in the immune system. ^23,40

With this in mind, tumors develop when normal cells undergo genetic alterations that affect growth points. This results in a disproportionate growth that eventually leads to the onset of the disease. As premalignant cells evolve to cancer cells, the environment surrounding the tumor coevolves as well, creating a dynamic circuit of tumormicroenvironment interaction. ^23,40

Approximately 80% of cancers are carcinomas, that is, cancers that originate in the epithelial tissue, and their main support is the stroma, which nourishes, protects and supports the epithelial tissue. It could be said that stroma is the connective tissue that forms the framework of an organ, and includes the extracellular matrix and the cells that synthesize it (fibroblasts, endothelial cells, etc.). ²³

Cancer cells communicate with their environment while exchanging soluble molecules with the paracrine stroma, which turns stroma into the support of the tumor and, therefore, facilitates its progression. It is worth mentioning that the success of the tumor depends on its ability to survive in an inhospitable microenvironment. Besides stromal cells, inflammatory cells may also be found in this microenvironment. ^39,40

Currently, cancer studies focus their efforts on finding a molecular mechanism that links mitochondrial mutations to tumor formation. Research seeks to increase the understanding of the molecular basis of cancer, with the purpose of finding new prevention, diagnosis and treatment methods for the disease.