Mitochondrial diseases
Mitochondrial diseases are a group of inherited disorders that arise from mutations in mitochondrial DNA (mtDNA), which is passed down maternally. These diseases can lead to a range of serious health issues, particularly affecting muscles and the central nervous system, and are often characterized by symptoms such as severe fatigue and muscle weakness. A unique aspect of mitochondrial diseases is heteroplasmy, where an individual may have more than one type of mtDNA present, potentially complicating the severity and expression of the disease within families. Diagnosis can be challenging, typically requiring genetic screening methods, such as polymerase chain reaction (PCR) on muscle biopsies.
Some well-known mitochondrial diseases include Leber hereditary optic neuropathy (LHON), which causes vision loss, and myoclonic epilepsy with ragged red fibers (MERRF), impacting brain and muscle function. These conditions exemplify the broader category of mitochondrial syndromes, which can vary widely in their expression and severity due to the complex nature of mtDNA mutations. Current experimental treatments are exploring ways to stimulate healthy mtDNA to regenerate damaged cells, although effective therapies for these diseases remain limited, highlighting the need for ongoing research into mitochondrial genetics and potential therapies.
Mitochondrial diseases
SIGNIFICANCE: Mitochondrial genes are few in number but are necessary for animal cells to grow and survive. Mutations in these genes can result in age-related degenerative disorders and serious diseases of muscles and the central nervous system for which there is no generally effective treatment. Mitochondrial diseases are transmitted maternally and are usually associated with heteroplasmy, a state in which more than one type of gene arrangement, or genotype, occurs in the same individual.
Mitochondrial Genetics and Disease
The unique arrangement of subunits making up individual genes is highly mutable, and thousands of different arrangements, or genotypes, are cataloged in humans. A tiny number of genes in animal cells are strictly inherited from the maternal parent and are found in the mitochondria, located in the cell’s cytoplasm, outside the nucleus, where most genetic information resides in nuclear DNA. Some variants in mitochondrial DNA (mtDNA) sequences can cause severe defects in sight, hearing, skeletal muscles, and the central nervous system. Symptoms of these diseases often include great fatigue. The diseases themselves are difficult to diagnose accurately, and they are currently impossible to treat effectively. Genetic screening methods based on polymerase chain reaction (PCR) technologies using muscle biopsies are essential for correct identification of these diseases.
A person normally inherits a single mtDNA type, but families are occasionally found in which multiple mtDNA sequences are present. This condition, called heteroplasmy, is often associated with mitochondrial disease. Heteroplasmy occurs in the major noncoding region of mtDNA without much impact, but if it exists in the genes that control the production of cellular energy, severe consequences result. Weak muscles and multiple organs are involved in most mitochondrial diseases, and there can be variable expression of a particular syndrome within the same family that may either increase or decrease with age. It is easiest to understand this problem by remembering that each cell contains a population of mitochondria, so there is the possibility that some mtDNAs will carry a particular mutation while others do not. Organs also require different amounts of adenosine triphosphate (ATP), the cell’s energy source produced in mitochondria. If the population of mutated mitochondria grows to outnumber the unmutated forms, most cells in a particular organ may appear diseased. This process has been called replicative segregation, and a mitochondrial disease is the result. Loss of mtDNA also occurs with increasing age, especially in the brain and heart.
Particular Mitochondrial Diseases
Mitochondrial diseases show a simple pattern of maternal inheritance. The first mitochondrial disease identified was Leber hereditary optic neuropathy (LHON), a condition associated with the sudden loss of vision when the optic nerve is damaged, usually occurring in a person’s early twenties. The damage is not reversible. Biologists now know that LHON is caused by at least four specific mutations that alter the mitochondrial proteins ND1, ND4, and CytB. A second mitochondrial syndrome is myoclonic epilepsy associated with ragged red fiber disease (MERRF), which affects the brain and muscles throughout the body. This disease, along with another syndrome called mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), is associated with particular mutations in mitochondrial transfer RNA (tRNA) genes that help produce proteins coded for by mtDNA. Leigh syndrome is a mitochondrial disease most commonly diagnosed in children that is tied to a mitochondrial change that causes the death of nervous system cells, which in turn leads to seizures, developmental delays, and cardiac and respiratory problems. Finally, deletions and duplications of mtDNA are associated with Kearns-Sayre syndrome (affecting the heart, other muscles, and the cerebellum), chronic progressive external ophthalmoplegia (CPEO; paralysis of the eye muscles), rare cases of diabetes, heart deficiencies, and certain types of deafness. Some of these conditions have been given specific names, but others have not.
Muscles are often affected by mitochondrial diseases because muscle cells are rich in mitochondria. New treatments for these diseases are based on stimulating undamaged mtDNA in certain muscle precursor cells, called satellite cells, to fuse to damaged muscle cells and regenerate the muscle fibers. Others try to prevent damaged mtDNA genomes from replicating biochemically in order to increase the number of good mtDNAs in any one cell. This last set of experiments has worked on cells in tissue culture but has not been used on humans. These approaches aim to alter the competitive ability of undamaged genes to exist in a cellular environment that normally favors damaged genes. Further advances in treatment will also require a better understanding of the atural ability of mtDNA to undergo genetic recombination and DNA repair.
Key Terms
- heteroplasmya mutation in which more than one set of gene products encoded by mitochondrial DNA (mtDNA) can be present in an individual organ or tissue type, a single cell, or a single mitochondrion
- maternal inheritancethe transmission pattern characteristically shown by mitochondrial diseases and mutations in mtDNA, where changes that occur in the mother’s genetic material are inherited directly by children of both sexes without masking or interference by the mtDNA of the father
- mitochondriasmall structures, or organelles, enclosed by double membranes found outside the nucleus, in the cytoplasm of all higher cells, that produce chemical power for the cells and harbor their own genetic material
- mitochondrial DNA (mtDNA)genetic material found uniquely in mitochondria, located outside the nucleus and therefore separate from the nuclear DNA
- replicative segregationa mechanism by which individual mtDNAs carrying different mutations can come to predominate in any one mitochondrion
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