When most people hear the acronym DNA, they immediately think of the genetic material that exists within the nucleus of their cells. However, there are two sources of DNA within most cells of the body - one in the nucleus, and another in the mitochondria. Although much about the genetic material of mitochondria remains a mystery, scientists have proposed the endosymbiotic theory to explain why these organelles have their own DNA and clinicians are, with difficulty, able to perform testing on and diagnose disorders of the mitochondrial DNA such as Leigh's Syndrome, Kearns-Sayre Syndrome, and MELAS.
With the discovery of mitochondrial DNA came the question of why this organelle has a separate genome. This question may have been answered by Boston University biologist Lynn Margulis, who came up with the now widely excepted endosymbiotic hypothesis (1). The endosymbiotic hypothesis suggests that mitochondria are the result of the endocytosis of aerobic bacterium (most likely alpha-proteobacterium) into anaerobic proto-eukaryotic cells billions of years ago (2). The two developed a mutualistic relationship because the aerobic bacterium contained enzymatic pathways that could metabolize the toxic oxygen to yield ATP for the anaerobic proto-eukaryotes, while the anaerobic proto-eukaryote provided protection and a constant source of metabolizable substrates for the aerobic prokaryote. Because of the evolutionary advantage conferred to the host cell, the aerobic prokaryote eventually became a part of the anaerobic proto-eukaryote. Over time, genes that had to do with independent replication were lost by the aerobic prokaryote and some of the genes necessary for respiration were transferred to its host cell's nuclear DNA. The result was an endosymbiont that has become the modern mitochondria. This way, Margulis was also able to explain why mitochondria are enclosed by two membranes. According to her hypothesis, the inner membrane of the mitochondria originates from the plasma membrane of the endocytosed prokaryotes and the outer membrane originates from the infolded plasma membrane of the anaerobic proto-eukaryotic host cell (1).
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Margulis's hypothesis continues to be a subject of experimentation worldwide, although most research generated after she published her endosymbiotic hypothesis supports her work (1). For instance, researchers have found that mitochondria have their own DNA and RNA polymerase, both of which are of the prokaryotic type. In addition, their ribosomes are not the 80s ribosomes of eukaryotes, but the 70s ribosomes common to bacteria. The mitochondrial chromosome not only structurally resembles the single circular DNA common to bacteria, but also replicates through binary fission like a bacterium would. In addition, while studying the inner membrane of the mitochondria scientists found that it contains multiple enzymes and electron transport molecules that resemble those found in the plasma membranes of modern prokaryotes. Most skeptics were convinced of the endosymbiotic hypothesis when mitochondrial DNA was sequenced. Mitochondrial DNA was shown to biochemically resemble Rickettsia prowazekii, the obligate intracellular alpha-proteobacterium that causes epidemic louse-borne typhus, more than any other organism that had been sequenced to date (3).
Mitochondrial DNA consists of 16,596 adenine, guanine, cytosine, and thymine base pairs arranged in a circular pattern that contains only thirty-seven genes (4). Thirteen of those genes encode for subunits of the respiratory chain, twenty-two genes code for transfer RNAs, and two genes code for the ribosomal RNA that translate mitochondrial RNA. All of the proteins not involved in DNA replication make up thirteen of the essential subunits of the respiratory chain (5). These subunits are a part of four out of the five respiratory chain complexes, which also contain proteins of nuclear origins. The respiratory chain is a series of steps that receive energy-rich hydrogens from FADH and NADH as they pass between Complexes I, III, and IV in the chain (4,5). This allows for the extrusion of protons from the mitochondria matrix to create an electrochemical gradient that Complex V uses to generate ATP.
Once a particular mutation that affects the respiratory chain is found, it can be traced through generations with relative ease. Because the egg contains cytoplasm rich with mitochondria and the sperm lose their cytoplasm during spermatogenesis, offspring will directly inherit their mitochondrial DNA from their mother (6). When pedigrees are created to explain a disorder, there will be a distinct pattern of maternal inheritance.
However, incomplete penetrance is observed in mitochondrial disorders because individuals with mitochondrial DNA mutations often have a combination of mutant and phenotypically normal DNA within the same cell, a state termed heteroplasmy. Studies have shown that within a single cell, if the percentage of mutant DNA does not reach a threshold amount, that cell will be phenotypically normal (5). In addition to explaining incomplete penetrance, researchers also believe this is a factor explaining why there is such a wide variation in the severity of phenotypic expression between individuals with the same mutation.
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To further complicate clinical diagnosis of mitochondrial disorders, there appears to be a weak correlation between genotype and phenotype (5). Individuals who clinically have the same disorder are often found to have different mutations in their mitochondrial DNA. On the other hand, the exact same mutation can cause extremely variable phenotypic expression. For example, the same point mutation can cause diabetes mellitus and deafness, chronic progressive external opthalmopegia, or severe encephalopathy with recurrent strokes and epilepsy.
In addition, disorders that affect mitochondrial function can also be secondary disorders, resulting from the mutation of autosomal genes involved in the respiratory chain or aging (5). In fact, only about ten to fifteen percent of mitochondrial diseases are caused by mutations in mitochondrial DNA (4).
In general, the way in which a mitochondrial mutation affects the body is predictable. Because of the vital role mitochondria play in the production of energy, mutations in mitochondrial DNA reduce the amount of energy available across the body (6). This predominately affects the organs of the muscular and nervous systems because of their high demands for energy, although the kidneys and liver are also affected with an increased frequency. Common symptoms within the mitochondrial disorders include external ophthalmoplegia, myopathy affecting proximal muscle groups, exercise intolerance, cardiomyopathy, sensorineural deafness, ptosis, loss of functional fibers in the optic nerve, pigmentary retinopathy, and diabetes mellitus (4). If a clinician recognizes a pattern of symptoms related to mitochondrial inherited dysfunctions, they can order a range of tests to diagnose and monitor the patient. These tests may include mitochondrial DNA sequencing (usually from a muscle biopsy, since there are a high number of mitochondria in muscle tissue), levels of co-enzymes, enzymes, and products found in the respiratory chain, and imaging studies of the mitochondrial electron transport chain (7).
Leigh's Syndrome, also known as subacute necrotizing encephalopathy, is one example of a mitochondrial disorder. Leigh's Syndrome is a progressive neurodegenerative disease that can be caused by mutations in mitochondrial, autosomal, or sex-linked genes (8). If the disorder is mitochondrial, the most common mutation is a point mutation at position 8993 on the ATP-ase gene. It is commonly found in infants, but has been noted in children and very rarely in adults. The disease presents itself as a failure to thrive with a progressive degradation of motor skills and ultimately death in the first years of life from demyelination, distinctive necrotic lesions throughout the brain, and diffuse brain atrophy.
Another example of a mitochondrial disorder is Kearns-Sayre syndrome. It is diagnosed based on a triad of symptoms: pigmentary retinopathy, a drooping of the eyelids and paralysis of the extraocular muscles known as progressive external opthalmopegia, and an onset of symptoms before the patient is twenty years old (9). In addition, to be diagnosed with Kearns-Sayre syndrome an individual must present with cardiac conduction block, cerebrospinal fluid protein concentrations of greater than 100mg/dL and/or a total loss of muscle coordination (ataxia) that is associated with cerebellar dysfunction (10). Patients also commonly present with dementia, loss of hearing, weakness in their limbs, diabetes mellitus, hypoparathyroidism, and a growth hormone deficiency that causes a short stature (9). There are more than 150 different deletions in the mitochondrial genome that have been associated with Kearns-Sayre syndrome, but a deletion of base pair 4977 is the most frequently seen.
A third example of a mitochondrial genetic disorder is mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). This disorder usually presents between the ages of ten and twenty, with the most common external symptom being migraines that produce vomiting (9). Often, these patients also experience "stroke-like" episodes caused by a failure in energy metabolism in the mitochondria. If this occurs in the occipital or temporal cortical regions of the brain, total loss of vision in the left or right eye (hemianopia) and/or weakness on one side of the body (hemiparesis) is commonly seen. Individuals with MELAS are typically of short stature and have hearing loss, diabetes mellitus, myopathy, and varying endocrinological dysfunctions. MELAS patients will usually have MRI findings of asymmetric T2 hyperintense lesions in the parietal lobes, occipital lobes, basal ganglia, and cerebellum displaying a characteristic laminar pattern. A substitution of adenine for guanine at position 3243 of the mitochondrial genome is the cause of MELAS in about eighty percent of all individuals.
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Sadly, it seems that the nature of mitochondrial DNA and its associated diseases is still very much a large question mark both diagnostically and scientifically. As outlined above, the diagnosis of mitochondrial DNA disorders is a very complicated process for clinicians due to the complexity of the inheritance and penetrance in individuals with these disorders. This difficulty in diagnosis seems to indicate an underlying lack of scientific knowledge about the nature of mitochondrial DNA. As research into mitochondrial DNA intensifies, improved detection and treatment of mitochondrial disorders should follow.