The ATP synthesis rate is strictly regulated according to the energy requirements of the cells. But the key question is what happens if the energy metabolism is malfunctioning and become to generate excessive amounts of ATP?
Additionally as malignant cells require excessive amount of ATP to synthesize new molecules in order to rapidly duplicate themselves, we will look at the role of the altered energy metabolism closely in this section to determine how the mitochondrial and glycolytic ATP synthesis pathyways contribute to the malignnat transformation and tumor progression.
Glycolytic ATP Synthesis & Cancer
In regular cells, the majority of the ATP is synthesized in special organelles called the mitochondria through oxidative phosphorylation and the rest in the cytosol -(intracellular fluid) through glycolysis.
80 years ago a central dogma of cancer was postulated by Otto Warburg who hypothesized that cancer, malignant growth, and tumor growth are caused by the fact that tumor cells mainly generate ATP by non‐oxidative breakdown of glucose or glycolysis. This is in contrast to "healthy" cells which mainly generate energy from oxidative breakdown of pyruvate. Hence and according to Warburg, cancer should be interpreted as a mitochondrial dysfunction. This concept has influenced basic cancer research throughout the 20th century. The hypothesis was set forth in his famous article On the Origin of Cancer Cells.
However recent research proved that Warburg's hypothesis was flawed. Articles such as Cancer metabolism: facts, fantasy, and fiction & Cancer's sweet tooth showed that mitochondria of cancer cells are functional and contribute to the ATP generation in cancer cells.
All tumor cell types show an enhanced glycolytic flux; however, not all have a diminished mitochondrial metabolic capacity. Therefore, the take-home message is that not all tumor cell types depend exclusively on glycolysis for ATP supply; some may equally or predominantly rely on oxidative phosphorylation. In consequence, the driving force for the enhanced glycolysis in tumor cells cannot be an energy deficiency induced only by a damaged oxidative phosphorylation. The accelerated cellular proliferation may also impose an energy deficiency (as well as a higher demand for glycolytic and Krebs cycle biosynthetic intermediaries), which can only be covered by an increased glycolysis together with an unperturbed oxidative phosphorylation.
New evidence show that most tumor cells initially depend on oxidative phosphorylation and when they become mature, their more hypoxic inner cores make a glycolytic switch compared to their actively proliferating outer rims which still heavily depend on oxidative phosphorylation to quickly generate ATP in high quantities. The transition is covered by Rodriguez‐Enriquez et al in Energy Metabolism Transition in Multi‐Cellular Human Tumor Spheroids.
It is recently documented that there is a symbiotic relationship between the glycolysis and oxidative phosphorylation depending cells in substrate utilization as covered by Semenza in Tumor metabolism: cancer cells give and take lactate:
Tumors contain well-oxygenated (aerobic) and porly oxygenated (hypoxic) regions, which were thought to utilize glucose for oxidative and glycolytic metabolism, respectively. In this issue of the JCI, Sonveaux et al. show that human cancer cells cultured under hypoxic conditions convert glucose to lactate and extrude it, whereas aerobic cancer cells take up lactate via monocarboxylate transporter 1 (MCT1) and utilize it for oxidative phosphorylation.
Generally the switch from oxidative phosphorylation to glycolysis during hypoxia is triggered by the HIF‐1α and both type of cells help each other.
Mitochondrial ATP Synthesis & Cancer
Mitochondria generate majority of the cell’s energy through oxidative phosphorylation. Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome which shows substantial similarity to bacterial genomes. Additionally, the mitochondrion has two different membranes, the outer and inner membranes. Depending on its metabolic needs, a cell may contain only a few or several hundreds or even thousands of mitochondria.
Evolutionary origin of mitochondria according to endosymbiont hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm. Endocytosis of a bacterium by an ancestral eukaryotic cell would generate an organelle with two membranes, the outer membrane derived from the eukaryotic plasma membrane and the inner one from the bacterial membrane. If an organelle capable of making its own decisions through its separate DNA that may affect very important functions and the viability of the cell, then there should be a very precise communication mechanism between the nucleus and the mitochondria in regulating the ATP synthesis rate.
As mitochondria plays the key role in ATP generation and if malignant transformation should be linked with excessive ATP generation, therefore mitochondria should also be more directly involved with cell division. Recently this link was confirmed by researchers at Texas A&M University who discovered a key role for mitochondria in An Increase in Mitochondrial DNA Promotes Nuclear DNA Replication in Yeast. This discovery was briefly explained in Yeast shows what drives cells to divide:
Mitochondria have been found to also be the driver with regard to cell division, according to a group of biochemists who say this discovery could play a large role in finding cures for many human diseases. The scientists studied yeast cells and found that mitochondria, which generate 90 percent of the cell’s energy, can be the deciding factor behind how fast cells divide. The finding changes the traditional view of the mitochondrion from an “energy depot” at the service of its larger cellular host to a “command center” that directs cell division. The research showed that when a yeast cell’s mitochondria decided to “turn on the switch”, the cell’s nucleus, which carries most of the genetic material, received the message and cell division began. So now we need to connect that link. We need to understand how and when the mitochondria send the message. If we know how the message is sent, we might be able to control it.
Incidence of Skeletal Muscle Cancers & the Role of Excessive ATP
If cancer is initiated only due to the mutations in the DNA as generally stated, then we must expect that it would affect different organs or tissues in the body to a comparable extent. However, while there is a relatively high incidence of cancer in most organs such as liver, breast, stomach, or in certain tissues such as the epithelial tissues, in adults, the incidence of cancers in certain other organs and tissues are extremely rare. (Because the developing tissues have different characteristics than mature tissues, we will be focusing only on adult cancers.)
While the heart is a sizeable organ, the primary cancer of the skeletal muscle cells (rhabdomyosarcoma) of the heart is so rare that it is almost unheard of. Additionally, while the skeletal muscle tissues make up 40% of our bodies, the incidence of rhabdomyosarcoma in adults is less than 0.1% of all cancers. It is worthwhile to try to determine why such cells almost never become malignant and whether lack of excessive ATP synthesis may help explain this.
Unlike most other cells, skeletal muscle cells contain enormous amount of mitochondria required to support high amounts of energy for contraction. For such reason, in order to generate excessive amount of ATP, several hundred mitochondria need to malfuntion simultaneously in skeletal musclecells which should be more rare compared to other cell types that contain much fewer number of mitochondria. Unlike most other cells which require higher rates of ATP synthesis only during cell division, skeletal muscle cells and in particular the heart consumes ATP on a continuously high rate so excessive build up would again be a smaller possibility. And finally skeletal muscle cells contain very high amount of creatine which enables them to convert and store excessive ATP in the form of phosphocreatine so that it can be converted back to ATP and used when needed.
For above reasons, compared to other types of cells in the body, the chance of excessive ATP build-up in skeletal muscle cells should be extremely rare. While they are also vulnerable to DNA mutations like other cells in the body and normally should be expected to have much higher incidence of cancer, perhaps this would help explain why skeletal muscle cells almost never become malignant.
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