Cancer Metabolism and Mitochondrial Dysfunction - An Overview

Introduction:

Mitochondria are the energy-producing structures in the cell that play an important role in the metabolism of energy, the maintenance of redox reactions (chemical reactions involving the transfer of electrons), and the regulation of programmed cell death called apoptosis. There are many alterations in mitochondrial function, such as TCA (tricarboxylic acid cycle) cycle enzyme defects, defective mitochondrial electron transport chain, mitochondrial DNA (deoxyribonucleic acid) genetic mutations, and oxidative stress, which can occur and lead to the development of cancer. Therefore, understanding these alterations can help in the development of targeted therapies (a type of treatment that targets specific proteins that help in the growth of cancer).

What Is Mitochondria?

Mitochondria are double-membrane structures of great importance. They consist of an outer membrane and an inner membrane that is folded and called cristae, creating spaces known as the inner membrane space and matrix. This organelle makes up 25 percent of the cell's structure. They play a crucial role in the processing of glucose, lipids, and glutamine, which aids in the production of energy through the TCA cycle. Besides, they have their own DNA (deoxyribonucleic acid) called mtDNA (mitochondrial DNA). Any mutation in this mtDNA or defects in the TCA cycle can contribute to human cancers.

What Is the Relationship Between Cancer Metabolism and Mitochondrial Dysfunction?

1. Mitochondrial TCA Cycle and Cancer: The TCA cycle is where the oxidation of carbohydrates, lipids, and amino acids takes place with the help of enzymes [isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), α-ketoglutarate (α-KG) dehydrogenase complex, and fumarate hydratase (FH)], and mutations in these enzymes can lead to the development of cancer. These disruptions can occur due to dysfunctional TCA enzymes and oxidative stress (an imbalance between reactive oxygen species and the body's ability to utilize them). Some of the mutations that can lead to the transformation of normal cells into cancer cells include:

• Mutations in the IDH2 gene can lead to the formation of D-2HG (D-2-hydroxyglutarate), and this abnormal accumulation can lead to modifications in the cell's DNA and inhibit the function of SDH, resulting in impaired mitochondrial respiration. Mutations of IDH1 and IDH2 are found in cancers such as gliomas (a type of brain cancer) and acute myeloid leukemia (a type of blood and bone marrow cancer).

• Mutations in SDH involve the abnormal accumulation of succinate, which inhibits the pyruvate dehydrogenase complex (PDH), which plays an important role in the breakdown of glucose. These mutations are found in renal carcinoma, colorectal carcinoma, ovarian cancer, and pituitary tumors.

• Mutation in FH can cause HIF1α (hypoxia-inducible factor 1-alpha) stabilization, which helps cells adapt to low oxygen levels but can contribute to tumor growth and progression by supporting angiogenesis. Heterozygous mutations lead to renal cell cancer and leiomyosarcoma (smooth muscle cancer).

2. Mitochondrial DNA Mutations and Cancer: The mtDNA is circular DNA with a size of 16.6 kilobases, which contains 37 genes responsible for the production of energy in the mitochondria. The coded region plays an important role in the respiratory chain, and the non-coding region called the D-loop (displacement loop) contains elements of transcription and replication. The respiratory chain consists of complexes 1, 3, 4, and 5. Sometimes, electron leakage from these complexes can lead to the production of harmful molecules called superoxide (O2−), which can cause oxidative stress. These can further be converted into harmful reactive oxygen species (ROS), disrupting cell signaling and causing DNA damage, leading to genomic instability and the development of cancer, along with resistance to many drugs.

The role of mtDNA is not fully understood; some studies have shown that it can either promote or inhibit the growth of tumors. For example, oncocytoma, which is a benign tumor, occurs due to a mutation in mtDNA, making it remain in a benign state. On the other hand, chromophobe renal cell carcinoma has additional mutations that cause it to become malignant.

3. Mitochondrial Oxidative Stress and Cancer: Mitochondrial oxidative phosphorylation is an energy- producing process that consumes about 90 percent of oxygen. During this process, oxygen is incompletely reduced, leading to the formation of superoxide radicals. However, these radicals are eliminated by antioxidant enzymes such as SOD2 (superoxide dismutase 2), GPX (glutathione peroxidase), GR (glutathione reductase), PRX (peroxiredoxin), and thioredoxin, which helps maintain the balance. Mutations in the mtDNA can cause increased electron leakage, resulting in higher levels of free radicals observed in cancer cells. These free radicals promote cell growth, damage DNA, and cause genetic instability, leading to cancer development. mtDNA mutations are significant factors in various disorders, including neurodegenerative disorders, aging, and cancer. Additionally, abnormal mitochondria, such as reduced size and disorganized folds, are also found in cancer cells.

4. Oncogene and Tumor Suppressor in Regulating Mitochondrial Function: Oncogenes (a group of genes that, when overexpressed, promote cell proliferation and contribute to the development of cancer) and tumor suppressor genes (a group of genes that regulate normal cell growth and inhibit tumor formation) also play a role in controlling the function of mitochondria. Some examples include:

• RAS: These belong to the family of small GTPases (guanosine triphosphatase), which includes HRAS, NRAS, and KRAS. They are involved in pathways of cell signaling such as proliferation, migration, etc. Mutations in these genes result in lung, pancreatic, or colorectal cancer. The mutant KRAS, which causes the development of cancer, affects the function of mitochondria, leading to an increase in oxidative stress.

• Cellular-MYC: It is a type of oncogenic transcription factor that causes the development of cancer. This factor also activates the genes responsible for mitochondrial dysfunction, resulting in tumorigenesis.

• P53: This is a tumor suppressor gene. In stressful conditions, it can lead to apoptosis and DNA damage. Mutations in the TP53 gene, which encodes P53, can cause aerobic glycolysis, oxidative stress, and increased buildup of lactate, all of which result in the development of cancer.

Conclusion:

Mitochondrial dysfunction can occur due to changes in mitochondrial DNA, enzymes involved in the TCA cycle, and the mitochondrial electron transport chain, contributing to the development of cancer. Additionally, tumor suppressor genes and oncogenes also play a role in its development. Severe changes in mitochondria can lead to cell death, whereas mild changes can cause cell proliferation. Therefore, understanding mitochondrial dysfunction helps in designing therapeutic agents against cancer.