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.

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

Cyclic vomiting syndrome may be related to genetic changes in mitochondrial DNA. Some of these 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. Defects in energy production may lead to symptoms during periods when the body requires more energy, such as when the immune system is fighting an infection. However, it remains unclear how changes in mitochondrial function are related to recurrent episodes of nausea and vomiting.

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 protein building blocks (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 the majority of the cell’s energy (ATP) in the mitochondria. The other genes provide instructions for making transfer RNA 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.

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 encephalopathy, 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 transfer RNA 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 transfer RNA 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.

nonsyndromic deafness

Mutations in two mitochondrial genes, MT-RNR1 and MT-TS1, are associated with nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body). These genes provide instructions for making different types of RNA. The MT-RNR1 gene provides instructions for a specific type of ribosomal RNA called 12S RNA. A particular form of transfer RNA, designated as tRNA^Ser(UCN), is formed from the MT-TS1 gene. Both of these RNA molecules help assemble amino acids into full-length, functioning proteins within mitochondria.

Mutations in the MT-RNR1 gene increase the risk of hearing loss, particularly in people who take prescription antibiotic medications called aminoglycosides. These antibiotics are typically used to treat life-threatening and chronic bacterial infections such as tuberculosis. Aminoglycosides kill bacteria by binding to their ribosomal RNA and disrupting the bacteria’s ability to make proteins. Common genetic changes in the MT-RNR1 gene can make the 12S RNA in human cells look similar to bacterial ribosomal RNA. As a result, aminoglycosides can target the altered 12S RNA just as they target bacterial ribosomal RNA. The antibiotic easily binds to the abnormal 12S RNA, which impairs the ability of mitochondria to produce proteins needed for oxidative phosphorylation. Researchers believe that this unintended effect of aminoglycosides may reduce the amount of ATP produced in mitochondria, increase the production of harmful byproducts, and eventually cause the cell to self-destruct (undergo apoptosis).

Nonsyndromic deafness also results from genetic changes in the MT-TS1 gene. Most of the mutations change a single building block (nucleotide) in the tRNA^Ser(UCN) molecule. These mutations likely disrupt the normal production of the molecule or alter its structure. As a result, less tRNA^Ser(UCN) is available to assemble proteins within mitochondria. These changes reduce the production of proteins needed for oxidative phosphorylation, which may impair the ability of mitochondria to make ATP.

Researchers have not determined why the effects of mutations in the MT-RNR1 and MT-TS1 genes are usually limited to cells in the inner ear that are essential for hearing. They believe that other genetic or environmental factors must play a role in the signs and symptoms associated with these mutations.

progressive external ophthalmoplegia

Mitochondrial DNA deletion or mutation can be involved in an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis). Some people with progressive external ophthalmoplegia have a single, large deletion of mitochondrial DNA. The most common deletion is 4,997 nucleotides, as in Kearns-Sayre syndrome (see above). Other people with the condition have a mutation in the mitochondrial gene MT-TL1. This gene provides instructions for making a specific transfer RNA (tRNA) called tRNA^Leu(UUR). This tRNA is found only in mitochondria and is important in assembling the proteins that carry out oxidative phosphorylation.

The A3243G mutation (described above), which is the same genetic change that has been associated with MELAS, is a relatively common cause of progressive external ophthalmoplegia. It is unclear how the same MT-TL1 gene mutation can result in different signs and symptoms. Mutations in the MT-TL1 gene impair the ability of mitochondria to make proteins, use oxygen, and produce energy, although researchers have not determined how these mutations lead to the specific signs and symptoms of progressive external ophthalmoplegia.

other disorders

Inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy for the cell efficiently. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues with high energy requirements (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, some frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

A buildup of somatic mutations in mitochondrial DNA has been associated with an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal aging process.

Mitochondrial DNA is typically diagrammed as a circular structure with genes and regulatory regions labeled.