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The role of mitochondria in the initiation and progression of cancer has long been debated, but it is generally accepted that mitochondria play an important role in cancer through replication and energy production. Identifying the important roles that mitochondria play in cancer development and progression can possibly help identify ways in which repairing mitochondrial function may be used for therapeutic benefit. Many cancer researchers tend to seek a reductionist approach in their research: the theory that condenses complex biological phenomena into their many parts, so we can understand a single cause and devise a cure. However, once reduction is done, there may be incentive for unification of theories to create a more holistic approach to cancer treatment. The mitochondria may be the gateway for this alternative approach.
This article will review the history of mitochondrial-cancer research as well as various, promising, non-toxic approaches to altering mitochondrial function in cancer cells, such as low-carbohydrate diet and fermented wheat germ extract nutrition.
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The mitochondria, home of the Krebs cycle or tricarboxylic acid cycle (TCA), are maternally-inherited, cytoplasmic organelles having evolved from symbiotic bacteria.1 Containing only 37 genes, they are known as the powerhouse of the cell for their role in producing chemical energy or adenosine triphosphate (ATP). By oxidizing (losing an electron) the fat, protein, and carbohydrates we consume through food and drink, they create energy-abundant molecules for the cell. These biochemical processes are known as cellular respiration. Within the TCA, substrates such as oxygen and glucose are converted, through enzymatic processes, first into pyruvate, then acetyl-CoA and ultimately lead to the production of an ATP molecule, water, and carbon dioxide.
Researchers at the United Mitochondrial Disease Foundation have reported that only three percent of genetic material per mitochondrion (one hundred in every three thousand) is required to produce up to 90% of the body's ATP.2 This efficiency apportions more than ninety-five percent of the mitochondrion to play other roles in regulating metabolic pathways. The mitochondria are genetically independent from the nucleus of the cell and communicate via nuclear transport and messenger proteins. Mitochondria are responsible for building and encoding nucleic acids and proteins responsible for cellular respiration, communicating with the nucleus, causing the cell to grow, function, and recycle its molecular building blocks through regulation of apoptosis pathways.3
Figure 1: Vander Heider MG et al. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009. 324(5930):1029–1033.6 This image shows normal cell respiration via OXPHOS, Anaerobic glycolysis, when oxygen is not available, and the cancer cell's energy cycle termed as the Warburg effect or 'Aerobic glycolysis'.
Mitochondria and the Warburg Effect
Normal cells produce energy through mitochondrial oxidative phosphorylation (OXPHOS). When oxygen is not available, they produce energy via the less efficient route of anaerobic glycolysis. In the 1920s, Otto Warburg observed that cancer cells do not produce energy in the efficient way that normal cells do. Rather, cancer cells produce most of their energy through an inefficient, high rate of glycolysis and glutaminolysis4 followed by fermentation of lactate into lactic acid. Glucose and glutamine metabolites are then diverted from producing ATP to a process to promote cell proliferation. This process was coined by Warburg himself as aerobic fermentation, which has been adapted to 'aerobic glycolysis', and commonly known as the Warburg Effect. Since lactate production is considered an indicator of respiratory insufficiency in biological systems,5 Warburg assessed aerobic production of lactate in cancer cells as a gauge of respiratory insufficiency. (Differentiated cells produce large amounts of lactate only under anaerobic conditions.) This observation, as we will see is a controversial one, not so much as to the involvement of the mitochondria in cancer, but at what point they become involved in the process, and whether they are functioning.
Biology professor, contemporary Warburg devotee, and cancer researcher, Dr. Thomas Seyfried outlines the key points of Warburg very well when he states that (i) insufficient respiration initiates tumorigenesis and ultimately cancer, (ii) energy through glycolysis gradually compensates for insufficient energy through respiration, (iii) cancer cells continue to ferment lactate in the presence of oxygen and (iv) respiratory insufficiency eventually becomes irreversible.5
Mitochondria and Cancer
Given the complexity of a disease, such as cancer, medical science might consider withholding its insistence on reductionism. With cancer, seeking out a single cure may be an over-simplification, as may claiming it to be one disease, or that there is only one cause. Depending on one's point of reference, cancer types differ broadly in such ways as the primary site, histopathology of cells, solid or liquid, genes involved, staging criteria, level of evidence, and perhaps, at what point the mitochondria become involved.7-14 Despite inconsistencies in the understanding of biochemical processes, cancer has been hailed for decades and supported by thousands of clinical trials by the somatic mutation theory (SMT), which cites that the initiating disease process is the result of nuclear mutations in oncogenes and tumor suppressor gene.9,15 This view is responsible for the ongoing development of cancer drugs that block specific genetic mutations, with some promise that one day a single drug could potentially treat all tumor types that share the same mutation.10
The mitochondrion theory appears to be the only cancer initiation theory that relates to all cancers, which, up to recently, has generally been explained in contrast with the SMT. Even genetics researchers Hanselmann and Welter, who wrote the highly cited paper Origin of Cancer: An Information, Energy, and Matter Disease,7 have been gathering evidence for and against alternative cancer etiology theories. In addition to the 1) SMT, these other theories are 2) microenvironment, 3) mitochondrion , and 4) aneuploidy categories, characterized by Hanselmann and Welter as each having 'supporting' and 'contradicting' evidence for the validity of the category itself. The Warburg Effect is detectable in all tumors, whereas the research shows that the microenvironment can cause cancer, or most cancer cells show mutations and most tumors show aneuploidy.7 However, this article will not debate reductionist theories and pit them against one another as the issue may not be in choosing the right one but in unifying them properly.5
All evidence supports the Warburg effect - whether causal or not - as constant in the initiation and/or progression of cancer. Some research argues against a reductionist model, while still upholding the majority view that cancer begins with the SMT, progresses to the microenvironment and then to the mitochondrion.9 It has been elucidated that cancer will select against the genes with the highest consumption of free energy. An alternate holistic model suggests that the underlying mechanisms of deregulated cellular metabolism are associated with, but not necessarily caused by, mitochondrial dysfunction, and that mitochondrial dysfunction can promote cancer progression to an apoptosis-resistant or invasive phenotype through a variety of mechanisms.12 Seyfried's holistic model is in accordance with the somatic mutation as an event that follows mitochondrion disruption. This research allows him to conclude that respiratory insufficiency is the origin of cancer, and that the other initiation theories, including the SMT, arise either directly or indirectly from insufficient respiration.12 In later research Seyfried postulates that a major weakness in the effort to cure cancer is due to the confusion surrounding the initiation theories. He believes that without a unifying agreement of how cancer arises, it becomes difficult to formulate a successful plan for effective treatment and prevention.5 Considering the aforementioned statistic of cancer initiation, from a reductionist perspective, it would be most appropriate to address the mitochondrion theory.
Mechanisms of Mitochondrial Disruption Provide Therapeutic Opportunities
Many vital cellular parameters are controlled by mitochondria. These include regulation of energy production, modulation of oxidation–reduction (redox) status, generation of reactive oxygen species (ROS), contribution to cytosolic biosynthetic precursors such as acetyl-CoA and pyrimidines, and initiation of apoptosis through the activation of the mitochondrial permeability transition pore and Cytochrome C. Changes in these parameters can shift the cell from a dormant state of differentiation to a proliferation state.1 Below, the mitochondrial disruptions are categorized but bear in mind that they overlap and should be considered a locus in the greater process or state of cancer initiation. There are many thorough investigations and positions on the role of mitochondrial dysfunction in cancer1,10,11,16,17 and following is a summary.
Genetic Mutations. Cancer cells have been shown to display genetic and epigenetic mutations that activate irregular programs that are important in development, stress response, wound healing and nutritional status.2 Cancer cells optimize the cancer cell environment by reprogramming adjacent cells for their benefit, using retrograde signaling.1 Some research claims that functional mitochondria are essential for the cancer cell.1,8,9 When mutations in mitochondrial genes are present, which is often in cancer cells, they alter the mitochondrial bioenergetic (i.e. oxygen rate and extracellular acidification rate) and biosynthetic state (i.e. cell proliferation), rather than inactivating mitochondrial energy metabolism (i.e. glycolysis, glutaminolysis, ATP).
Mitochondria regulate the transcription factor Hypoxia-Inducible Factor 1 (HIF-1), which induces glycolysis under hypoxic conditions allowing cancer to thrive. HIF-1 is increasingly studied because it allows for survival and proliferation of cancerous cells due to its angiogenic properties thus inhibition of HIF-1 potentially could prevent the spread of cancer.1,4
Enzyme Defects. Cancer cells require altered metabolism to efficiently incorporate nutrients into biomass and support abnormal proliferation. In addition, the survival of tumor cells outside of normal tissue context requires adaptation of metabolism to different microenvironments. Warburg theorized that to treat cancer is not to target mutated genes but enzymes that cancer cells depend upon more than normal cells for tumor cell growth, survival and proliferation. They are present in virtually all cancers.18 There are several metabolic enzyme defects that give way to some existing treatments targeting these enzymes.13 However, long-term success with this approach may depend on understanding why specific metabolic pathways are important for cancer cells and which patients are likely to respond.19
Redox Reactions and Glycolysis. Reactions involving electron transfers are known as oxidation-reduction reactions or redox reactions for which OXPHOS is the metabolic pathway. A redox reaction occurs as a result of two smaller reactions; one molecule loses one or more electrons, and simultaneously gains an oxygen atom, to become oxidized and another molecule gains an electron and loses an oxygen atom to become reduced. Cancer cells have an amazing tendency to reprogram their metabolic capability by inhibiting OXPHOS to elevate glycolytic metabolism. There is a therapeutic opportunity for inhibiting glycolysis to shift cellular metabolism to OXPHOS20 oxidizing NADH to ATP instead.
Reactive Oxygen Species and Antioxidants. The increase of ROS in cancer cells is linked to many irregularities in cellular functions such as cell proliferation, migration, differentiation and apoptosis.21 The increased promotion of ROS in tumor cells with mitochondrial dysfunction may make them more liable to further oxidative stress, compared to normal cells with lower ROS yield. High production of mitochondrial ROS in hypoxic cells has been shown to link cancer to ischemic disorders.21
NADPH is required for the reduction of hydroperoxides by glutathione and glutathione peroxidases by the mitochondria. When mitochondrial ROS production is too high, it is toxic to the cell and can induce apoptosis or necrosis as well as contribute to new abnormal tissue. The tumor suppressor p53 can arrest growth and initiate apoptosis. Inactivation of p53 should decrease OXPHOS in favor of glycolysis, increase ROS production and inhibit apoptosis. In other contexts, p53 activation can also induce cellular deterioration. Excessive shortening of chromosomal telomeres activates p53, which results in mitochondrial dysfunction, increased ROS levels, and deterioration.1
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