Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. Oxidative phosphorylation is a process that uses oxygen and simple sugars to create adenosine triphosphate ATP , the cell's main energy source. These types of RNA help assemble protein building blocks amino acids into functioning proteins.
The following chromosomal conditions are associated with changes in the structure or number of copies of mitochondrial dna. Changes in mitochondrial DNA are among the best-studied genetic factors associated with age-related hearing loss. This form of hearing loss develops with age and can begin as early as a person's thirties or forties.
It typically affects both ears and worsens gradually over time, making it difficult to understand speech and hear other sounds. This condition results from a combination of genetic, environmental, and lifestyle factors, many of which have not been identified. As people age, mitochondrial DNA accumulates damaging mutations, including deletions and other changes.
This damage results from a buildup of harmful molecules called reactive oxygen species, which are byproducts of energy production in mitochondria. Mitochondrial DNA is especially vulnerable because it has a limited ability to repair itself.
As a result, reactive oxygen species easily damage mitochondrial DNA, causing cells to malfunction and ultimately to die. Cells that have high energy demands, such as those in the inner ear that are critical for hearing, are particularly sensitive to the effects of mitochondrial DNA damage. This damage can irreversibly alter the function of the inner ear, leading to hearing loss.
Some cases of cyclic vomiting syndrome, particularly those that begin in childhood, may be related to changes in mitochondrial DNA. This disorder causes recurrent episodes of nausea, vomiting, and tiredness lethargy. Some of the genetic changes alter single DNA building blocks nucleotides , whereas others rearrange larger segments of mitochondrial DNA. These changes likely impair the ability of mitochondria to produce energy. Researchers speculate that the impaired mitochondria may affect certain cells of the autonomic nervous system, which is the part of the nervous system that controls involuntary body functions such as heart rate, blood pressure, and digestion.
However, it remains unclear how these changes could cause the recurrent episodes characteristic of cyclic vomiting syndrome. Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency, which is a condition that can affect several parts of the body, including the muscles used for movement skeletal muscles , the heart, the brain, or the liver.
The mitochondrial genes associated with cytochrome c oxidase deficiency provide instructions for making proteins that are part of a large enzyme group complex called cytochrome c oxidase also known as complex IV.
Cytochrome c oxidase is responsible for the last step in oxidative phosphorylation before the generation of ATP. The mtDNA mutations that cause this condition alter the proteins that make up cytochrome c oxidase.
As a result, cytochrome c oxidase cannot function. A lack of functional cytochrome c oxidase disrupts oxidative phosphorylation, causing a decrease in ATP production. Researchers believe that impaired oxidative phosphorylation can lead to cell death in tissues that require large amounts of energy, such as the brain, muscles, and heart.
Cell death in these and other sensitive tissues likely contribute to the features of cytochrome c oxidase deficiency. The deletions range from 1, to 10, nucleotides, and the most common deletion is 4, nucleotides. Kearns-Sayre syndrome primarily affects the eyes, causing weakness of the eye muscles ophthalmoplegia and breakdown of the light-sensing tissue at the back of the eye retinopathy.
The mitochondrial DNA deletions result in the loss of genes that produce proteins required for oxidative phosphorylation, causing a decrease in cellular energy production. Researchers have not determined how these deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome, although the features of the condition are probably related to a lack of cellular energy.
It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy. These genes provide instructions for making proteins that are part of a large enzyme complex.
This enzyme, known as complex I, is necessary for oxidative phosphorylation. The mutations responsible for Leber hereditary optic neuropathy change single amino acids in these proteins, which may affect the generation of ATP within mitochondria. However, it remains unclear why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain the optic nerve. Additional genetic and environmental factors probably contribute to vision loss and the other medical problems associated with Leber hereditary optic neuropathy.
Mutations in one of several different mitochondrial genes can cause Leigh syndrome, which is a progressive brain disorder that usually appears in infancy or early childhood.
Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing. Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation. For example, the most commonly mutated mitochondrial gene in Leigh syndrome, MT-ATP6 , provides instructions for a protein that makes up one part of complex V, an important enzyme in oxidative phosphorylation that generates ATP in the mitochondria.
The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.
Many of these proteins play an important role in oxidative phosphorylation. The mitochondrial gene mutations that cause Leigh syndrome impair oxidative phosphorylation. Although the mechanism is unclear, it is thought that impaired oxidative phosphorylation can lead to cell death in sensitive tissues, which may cause the signs and symptoms of Leigh syndrome. People with this condition have diabetes and sometimes hearing loss, particularly of high tones.
In certain cells in the pancreas beta cells , mitochondria help monitor blood sugar levels. In response to high levels of sugar, mitochondria help trigger the release of a hormone called insulin, which controls blood sugar levels.
Researchers believe that the disruption of mitochondrial function lessens the mitochondria's ability to help trigger insulin release. In people with MIDD, diabetes results when the beta cells do not produce enough insulin to regulate blood sugar effectively.
Researchers have not determined how mutations in these genes lead to hearing loss. When caused by mutations in this gene, the condition is usually characterized by muscle weakness myopathy and pain, especially during exercise exercise intolerance. More severely affected individuals may have problems with other body systems, including the liver, kidneys, heart, and brain.
This protein is one component of complex III, one of several complexes that carry out oxidative phosphorylation. Most MT-CYB gene mutations involved in mitochondrial complex III deficiency change single amino acids in the cytochrome b protein or lead to an abnormally short protein.
These cytochrome b alterations impair the formation of complex III, severely reducing the complex's activity and oxidative phosphorylation. Damage to the skeletal muscles or other tissues and organs caused by the lack of cellular energy leads to the features of mitochondrial complex III deficiency. Some of these genes provide instructions for making proteins that are part of a large enzyme complex, called complex I, that is necessary for oxidative phosphorylation. This mutation, written as AG, replaces the nucleotide adenine with the nucleotide guanine at position in the MT-TL1 gene.
The mutations that cause MELAS impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Die Elementarorganismen und ihre Beziehungen zu den Zellen. Second Extended Edition.
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DiMauro, Salvatore. Ernster, Lars, and Gottfried Schatz. Gray, Michael W. Holt, Ian J. Harding, and John A. Jansen, Robert P. Katsnelson, Alla. Lane, Nick. Molloy, P. Linnane, and H. Nass, Margit M. Fixation and Electron Staining Reactions. Sagan, Lynn. Sanger, Frederick. Sharpley, Mark S. John, Justin C.
Tuppen, Helen A. Blakely, Douglass M. Turnbull, and Robert W. Van Blerkom, Jonathan. Wallace, Douglas C. Lott, Judy A. Hodge, Theodore G. One of these mitochondria-associated disorders is Leber hereditary optic neuropathy LHON , which leads to a loss of vision in both eyes and is most commonly associated with a homoplasmic mitochondrial DNA mutation, although heteroplasmic transmission also occurs Man et al. These findings point to the likely involvement of other genes and environmental factors.
Similarly, a homoplasmic mutation in a mitochondrial genome-encoded ribosomal RNA , called RNR1, causes postlingual deafness deafness that occurs after three years of age, when a child has already learned to speak. The clinical symptoms of this disease are associated with the administration of a particular type of antibiotic Prezant et al.
Therefore, environmental factors also contribute to the phenotypes associated with this mitochondrial mutation. What are some clues that may suggest a mitochondrial link to disease? Some clinical features include a maternal family history and the involvement of several different tissues. Furthermore, because mitochondria function as the powerhouses of our cells, mitochondrial mutations often lead to more pronounced phenotypes in tissues that have high energy demands, such as brain, retinal, skeletal muscle, and cardiac muscle tissues.
A number of clinical syndromes are currently believed to be associated with mitochondrial disease. Possible examples include Pearson syndrome, Leigh syndrome, progressive external ophthalmoplegia, exercise-induced muscle pain , fatigue, and rhabdomyolysis.
As previously mentioned, mitochondrial DNA in humans is always inherited from a person's mother Figure 4. As a result, we share our mitochondrial DNA sequence with our mothers, brothers, sisters, maternal grandmothers, maternal aunts and uncles, and other maternal relatives. Due to the high mutation rates associated with mitochondrial DNA, significant variability exists in mitochondrial DNA sequences among unrelated individuals.
However, the mitochondrial DNA sequences of maternally related individuals, such as a grandmother and her grandson or granddaughter, are very similar and can be easily matched. Mitochondrial DNA sequence data has proved extremely useful in human rights cases, as it is a great a tool for establishing the identity of individuals who have been separated from their families. This approach has been very successful for the following reasons Owens et al. One of the most prominent researchers to use mitochondrial DNA sequence data to tackle human rights issues is Dr.
A particularly interesting example of Dr. King's work occurred in Argentina. As a result of a military dictatorship that overthrew the existing Argentinean government in , thousands of citizens disappeared between and , including infants and children who were abducted along with their parents.
In addition, some children were born to women who were pregnant at the time of their kidnappings. After the military dictatorship was defeated, a new government commission predicted that at least 8, and possibly as many as 30, people had been kidnapped, including documented infants and children. In , the grandmothers of these orphans formed the Associacion de Abuelas de Plaza de Mayo in an effort to identify their missing grandchildren, many of whom were illegally adopted by military families.
In , King used mitochondrial DNA sequence data to reunite some of these Argentinean orphans with their grandmothers. King collected blood samples from orphaned children and from women who had lost their children and grandchildren. Using mitochondrial DNA sequence data, she then matched more than 60 orphans with their biological families. In fact, as recently as , a young Argentinean man named Guillermo was finally reunited with his grandmother and sister.
Guillermo's parents were kidnapped by security forces in October ; Guillermo's mother, Patricia, was pregnant at the time of her kidnapping, and Guillermo was born one month later. Guillermo provided a blood sample to King's group, and his mitochondrial DNA sequence was a perfect match to that of one woman out of 2, in the database: Rosa, the mother of Patricia.
As an additional test, the researchers obtained a DNA sample from Mariana, the known daughter of Patricia, who was at a friend's house on the day her parents were kidnapped.
As shown by this example, mitochondrial DNA sequences can be used to establish family ties with maternal relatives, even when both of a person's parents are missing. Over the years, a probable role for mitochondria in both aging and cancer has emerged.
As a byproduct of their role as powerhouses of our cells, mitochondria generate reactive oxygen species ROS. ROS production has been proposed to cause somatic mitochondrial mutations. This can lead to a cycle in which ROS generate mutations, which in turn lead to disregulation of respiration and accumulation of more mutations.
Indeed, ROS production contributes to tissue aging due to decreased metabolic function and energy production, increased cell death, and a decreased capacity to replicate the genome. In , a link between colorectal cancer and somatic mitochondrial mutations was established by Polyak and colleagues.
These researchers cultured colorectal cancer cells taken from the tumors of 10 colorectal cancer patients. They then compared the mitochondrial DNA sequences of the tumor cell lines to the mitochondrial DNA sequences of cells from neighboring normal colon tissue from the same patient. This side-by-side comparison was used to identify somatic mutations that had occurred in the mitochondrial DNA of the tumor cells.
The researchers found that seven cell lines had acquired somatic mutations in their mitochondrial DNA sequences. Three of the cell lines had acquired a single mutation, and four had acquired between two and three mutations, for a total of twelve mutations. Eight of the mutations were in protein-encoding mitochondrial genes, and four of the mutations were in mitochondrial ribosomal RNA rRNA genes.
To confirm that the mitochondrial mutations had occurred in the tumors themselves and not during the culturing of the cells, the researchers next isolated DNA from the original tumor tissue and sequenced the mitochondrial DNA directly. Tumor tissue was only available for five out of the seven patients with mitochondrial mutations in their cultured cells.
In all five cases, however, the same mutations were present in the primary tumor as in the cultured tumor cells.
Furthermore, the mitochondrial mutations were all homoplasmic in both the primary tumor and in the cultured cells. Based on these findings, Polyak and colleagues suggested that the somatic mitochondrial mutations might have provided a growth advantage to a single cell that subsequently proliferated more rapidly than the surrounding cells. Furthermore, based on the homoplasmic nature of the mitochondrial DNA mutation, they suggested that the mutation might have provided a replicative advantage to the mutant mitochondrial genome.
In the years that followed, a number of other studies also established associations between somatic mitochondrial mutations and various forms of cancer, including leukemias and solid tumors. However, a causative link between mitochondrial mutations and cancer has not yet been firmly established. Clearly, the role of the mitochondrial genome must be considered with respect to human genetic disease.
The heterogeneity of the mitochondrial genome presents many unmet challenges to researchers. However, emerging technologies are likely to aid the discovery of underlying genetic mechanisms linking these powerhouses to neurodegenerative disease, cancer, diabetes, and aging. Mitochondrial DNA plays important roles in other areas of genetics as well. For example, it has been used to address questions about how the widespread distribution of humans in the world today was established.
Because mitochondria are passed exclusively through the maternal lineage and there is little recombination in the mitochondrial genome, variation in the mitochondrial genome as well as in the Y chromosome in the case of paternal lineages has been used to delineate how and when humans migrated and occupied the world.
Studying the mitochondrial genome in individuals from distinct geographic origins has made it possible to establish that the human populations of today are all derived from a small group of individuals that left Africa approximately , years ago Ingman et al.
Though small in size, the mitochondrial genome is responsible for ensuring that the powerhouses of our cells function properly. This circular genome is both more plentiful than its nuclear counterpart and more prone to mutation. Currently, it is difficult to predict the way in which mtDNA mutations will pass from mother to child due to the interplay between the mitochondrial and nuclear genomes.
It is clear, however, that these mutations are more pronounced in tissues that place high energy demands on mitochondria. In spite of this, mtDNA mutations are not entirely a bad thing. In fact, the variability introduced into mtDNA sequences by these mutations helps link family members to one another and has proven useful in reuniting missing children with their mothers, grandmothers, brothers, and sisters.
Much remains to be learned about mtDNA, however, and continued study of this fascinating genome will continue to expand our understanding of human disease and human history for years to come. Ingman, M. Mitochondrial genome variation and the origin of modern humans. Nature , doi Man, P. The epidemiology of Leber hereditary optic neuropathy in the North East of England. American Journal of Human Genetics 72,
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