Mitochondrial DNA mutations
Mitochondrial DNA (mtDNA) mutations are alterations in the genetic material found within mitochondria, the energy-producing organelles in eukaryotic cells. Unlike nuclear DNA, mtDNA mutates at a significantly higher rate, approximately ten times faster, due to factors like a less efficient DNA repair process and exposure to reactive oxygen species produced during energy generation. These mutations can lead to mitochondrial dysfunction, which is implicated in various cancers, including breast, colorectal, and lung cancers.
There are two main classes of mtDNA mutations: severe mutations that disrupt cellular respiration and promote tumor growth by increasing reactive oxygen species, and milder mutations that help tumors adapt as they progress. Mitochondrial mutations can be inherited maternally and may predispose individuals to certain cancers. Research has linked specific mtDNA mutations to an increased risk of developing cancers and have also shown that analyzing these mutations can aid in monitoring tumor progression and treatment responses.
By focusing on mtDNA mutations, scientists are exploring potential therapeutic targets, such as inhibiting glycolysis and restoring the normal programmed cell death pathways in cancer cells. Understanding these mutations offers valuable insights into cancer biology and potential avenues for improving diagnosis and treatment strategies.
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Subject Terms
Mitochondrial DNA mutations
ALSO KNOWN AS: Mitochondrial heteroplasmy (different mitochondrial mutations are present), homoplasmy (only a single type of mitochondrial DNA, or deoxyribonucleic acid, sequence is present)
RELATED CONDITIONS: Warburg effect
DEFINITION: Mitochondria are organelles in eukaryotic cells that produce energy (adenosine triphosphate, or ATP) by oxidative phosphorylation. Mitochondria are made from the proteins encoded by nuclear genes and genes from the mitochondrion’s own genome. The mitochondrial genome is sixteen kilobase pairs and encodes thirty-seven genes, which function in the mitochondrion. The majority of proteins in the mitochondrion are products of nuclear-encoded genes. There are multiple copies of the mitochondrial genome in each mitochondrion and multiple mitochondria in each cell. Mitochondrial DNA mutates at a high rate, and mitochondrial dysfunction is a factor in the development of cancers. Many defects in mitochondrial function are found in tumors.
The mutation process: Mitochondrial DNA (mtDNA) mutates at a rate about ten times greater than that of nuclear DNA. Likely reasons for this high mutation rate are an error-prone DNA polymerase, inefficient DNA repair enzymes, and exposure to mutagens such as oxygen radicals that are present in the mitochondrion.
Cancer cells have metabolic imbalances and a decrease in mitochondrial apoptosis (programmed, or planned, cell death). In cancer, the rapid growth of tumors is possible because of the shift in the mitochondria to glycolysis rather than the normal respiration (oxidative phosphorylation) to make ATP. Changes are observed in cancer cells, including the production of more of the rate-limiting enzymes of glycolysis and the accumulation of mutations in mitochondrial DNA. Often these mutations are in genes involved in mitochondrial respiration and ATP generation. In addition, sometimes people have mitochondrial mutations (germ-line mutations) that predispose that person to develop cancer. It is thought that most mtDNA mutations are acquired during or after the start of the cancer.
Mitochondrial DNA mutations are divided into two classes. The first class is severe mutations that inhibit oxidative phosphorylation and cause an increase in reactive oxygen species. Such mutations will promote tumor growth. The second class is milder mutations, which will allow tumors to adapt to new microenvironments as a tumor progresses and metastasizes.
Cancer cells have metabolic imbalances and decreased mitochondrial apoptosis (programmed or planned cell death). In cancer, the rapid growth of tumors is possible because of the shift in the mitochondria to glycolysis rather than normal respiration (oxidative phosphorylation) to make ATP. Changes are observed in cancer cells, including the production of more rate-limiting enzymes of glycolysis and the accumulation of mutations in mitochondrial DNA. Often, these mutations are in genes involved in mitochondrial respiration and ATP generation. Sometimes, people have mitochondrial mutations (germ-line mutations) that predispose them to develop cancer. Most mtDNA mutations are acquired during or after the start of the tumor.
Associated cancers: Changes in mtDNA sequences have been found in many different cancers, including lung, breast, pancreatic, gastric, colorectal, thyroid, cervical, and prostate cancers. Mutations in the nuclear DNA-encoded mitochondrial genes for fumarate hydratase and succinate dehydrogenase are associated with uterine leiomyomas and paragangliomas. Studies have shown that the presence of certain mitochondrial DNA sequences (single nucleotide polymorphisms) is associated with an increased (or, for other sequences, a decreased) risk of developing breast cancer. Germ-line mutations in mitochondrial DNA at nucleotides 10398 and 16189 are linked to breast and endometrial cancer. If the mitochondrial electron transport chain reactions are not functioning well, reactive oxygen species are made that cause oxidative stress and increase the risk of developing breast cancer. Other germ-line mtDNA mutations are associated with an increased risk of prostate cancer. Note that mutations in mtDNA show maternal inheritance because sperm mitochondria are generally eliminated from the embryo, so mtDNA comes from the mother via the egg.
Mutations and monitoring: Somatic mutations in the displacement loop (D-loop, where the mtDNA starts replication) occur frequently in colorectal cancers. There are hot spots in the D-loop where mtDNA mutations frequently occur. A colorectal tumor with a mutation in the D-loop is associated with a poor prognosis and resistance to fluorouracil-based adjuvant chemotherapy in Stage III colon cancers. Thus, changes in mtDNA sequences are involved in the initiation and progression of cancers. Examining the mtDNA mutations in populations of cancer cells may be useful in monitoring tumor progression. Analysis of these mutations may be useful for diagnosing and treating cancer. Targets for drug treatment include glycolysis and inducing apoptosis in mitochondria.
Bibliography
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