Mitochondrial DNA

What is mitochondrial DNA?

Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. In humans, mitochondrial DNA spans about 16,500 DNA building blocks (base pairs), representing a small fraction of the total DNA in cells.
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. The remaining genes provide instructions for making molecules called transfer RNA (tRNA) and ribosomal RNA (rRNA), which are chemical cousins of DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins.
Mitochondrial genes are among the estimated 20,000 to 25,000 total genes in the human genome.

How are changes in mitochondrial DNA related to health conditions?

Many genetic conditions are related to changes in particular mitochondrial genes. This list of disorders associated with mitochondrial genes provides links to additional information.
The following conditions are related to changes in the structure of mitochondrial DNA.

cancers

Mitochondrial DNA is prone to somatic mutations, which are a type of noninherited mutation. Somatic mutations occur in the DNA of certain cells during a person's lifetime and typically are not passed to future generations. There is limited evidence linking somatic mutations in mitochondrial DNA with certain cancers, including breast, colon, stomach, liver, and kidney tumors. These mutations might also be associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma).
It is possible that somatic mutations in mitochondrial DNA increase the production of potentially harmful molecules called reactive oxygen species. Mitochondrial DNA is particularly vulnerable to the effects of these molecules and has a limited ability to repair itself. As a result, reactive oxygen species easily damage mitochondrial DNA, causing a buildup of additional somatic mutations. Researchers are investigating how these mutations could be related to uncontrolled cell division and the growth of cancerous tumors.

cyclic vomiting syndrome

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 cause the recurrent episodes characteristic of cyclic vomiting syndrome.

cytochrome c oxidase deficiency

Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency (also known as complex IV 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 subunit proteins that are part of a large enzyme 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 mitochondrial DNA mutations that cause this condition alter the subunit proteins that make up cytochrome c oxidase. As a result, cytochrome c oxidase cannot function. A lack of functional cytochrome c oxidase disrupts the last step of 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.

Kearns-Sayre syndrome

Most people with Kearns-Sayre syndrome have a single, large deletion of mitochondrial DNA. The deletions range from 1,000 to 10,000 nucleotides, and the most common deletion is 4,997 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.

Leber hereditary optic neuropathy

Mutations in four mitochondrial genes, MT-ND1, MT-ND4, MT-ND4L, and MT-ND6, have been identified in people with Leber hereditary optic neuropathy. 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.

Leigh syndrome

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.

maternally inherited diabetes and deafness

Mutations in at least three mitochondrial genes, MT-TL1, MT-TK, and MT-TE, can cause mitochondrial diabetes and deafness (MIDD). People with this condition have diabetes and sometimes hearing loss, particularly of high tones. The MT-TL1, MT-TK, and MT-TE genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. 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. The MT-TL1, MT-TK, and MT-TE gene mutations associated with MIDD slow protein production in mitochondria and impair their function. 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.

mitochondrial complex III deficiency

Mutations in the MT-CYB gene found in mitochondrial DNA can cause mitochondrial complex III deficiency. 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.
The MT-CYB gene provides instructions for making a protein called cytochrome b. 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.

mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Mutations in at least five mitochondrial genes, MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV, can cause the characteristic features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). 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. The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.
One particular mutation in the MT-TL1 gene causes more than 80 percent of all cases of MELAS. This mutation, written as A3243G, replaces the nucleotide adenine with the nucleotide guanine at position 3243 in the MT-TL1 gene.
The mutations that cause MELAS impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

myoclonic epilepsy with ragged-red fibers

Mutations in at least four mitochondrial genes, MT-TK, MT-TL1, MT-TH, and MT-TS1, can cause the signs and symptoms of myoclonic epilepsy with ragged-red fibers (MERRF). These genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.
One particular mutation in the MT-TK gene causes more than 80 percent of all cases of MERRF. This mutation, written as A8344G, replaces the nucleotide adenine with the nucleotide guanine at position 8344 in the MT-TK gene.
Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes impair the ability of mitochondria to make proteins, use oxygen, and produce energy. It remains unclear how mutations in these genes lead to the muscle problems and neurological features of MERRF.

neuropathy, ataxia, and retinitis pigmentosa

Mutations in one mitochondrial gene, MT-ATP6, have been found in people with neuropathy, ataxia, and retinitis pigmentosa (NARP). The MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function. This protein forms one part (subunit) of an enzyme called ATP synthase. This enzyme, which is also known as complex V, is responsible for the last step of oxidative phosphorylation, in which a molecule called adenosine diphosphate (ADP) is converted to ATP. Mutations in the MT-ATP6 gene alter the structure or function of ATP synthase, reducing the ability of mitochondria to make ATP. It is unclear how this disruption in mitochondrial energy production leads to muscle weakness, vision loss, and the other specific features of NARP.