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Mitochondrial Diseases

Mitochondrial Genes And Disease

Mitochondrial DNA encodes approximately 3 percent of mitochondrial proteins. The relative contribution of the mitochondrial and nuclear genomes Figure 2. Muscle biopsy of mitochondrial myopathy patient (modified Gomori trichrome stain) with ragged red fiber showing disorganization and mitochondrial proliferation. Mitochondria stain red. Other muscle fibers also have increased numbers of mitochondria. in coding for electron transport chain subunits is detailed in Figure 1. Human mtDNA contains 16,569 nucleotide bases and encodes thirteen polypeptides of the electron transport chain, twenty-two transfer RNAs (tRNAs) and two ribosomal RNAs (rRNAs). In addition, mtDNA has a control region (termed the D-loop), which contains considerable genetic variation. The D-loop forms the basis of forensic medicine DNA identification and has been very useful in the molecular anthropological study of human origins.

In 1988 the first human disease associated with mtDNA deletions was reported. These patients suffered from muscle and brain diseases with ragged red fiber muscle disease (myopathy), with or without progressive neurological deterioration. Ragged red fibers are muscle fibers, that have a disorganized structure and an excess of abnormal mitochondria and that stain red when treated with a histochemical stain called modified Gomori trichrome (Figure 2). In 1988 Kearns-Sayre syndrome, which primarily affects the muscles, heart, and brain, was found to be due to mtDNA deletions or duplications. About the same time, the maternally inherited disorder Leber's hereditary optic atrophy was traced to point mutations in mitochondrial DNA encoding subunits of complex I of the electron transport chain.


Organ or System Diseased Symptoms
brain stroke, seizures, dementia, ataxia, developmental delay
muscle weakness, pain, fatigue
nerve neuropathy
heart cardiomyopathy, heart failure, heart block, arrhythmia
pancreas diabetes, pancreatitis
eye retinopathy, optic neuropathy
hearing sensorineural deafness
kidney renal failure
GI system diarrhea, pseudo-obstruction, dysmotility

Table 1.

Mitochondrial diseases tend to affect multiple organ systems. The cells and organs most severely affected are those most heavily dependent on ATP, such as those listed in Table 1. Patients will frequently have multiple symptoms or signs, a circumstance that often causes confusion in diagnosis and treatment.

One of the more common presentations of mitochondrial disease in infants and young children is Leigh's disease, first described by the pathologist Dennis Leigh in 1951. This progressive disease primarily affects the brain, with episodic deterioration that is often triggered by mild viral illnesses. Other organ systems are often involved, and there is often high blood or brain lactic acid as a result of a failure in oxidative metabolism (lactic acid is formed from glucose in the absence of oxygen). Figure 1 details the sites of metabolic defect and the percentages of cases affected in cases of Leigh's syndrome. Complex I and IV defects are autosomal recessive diseases, with the culprit genes residing on the nuclear chromosomes. Complex V mutations are mtDNA inherited, and another 25 percent of cases are X-linked, due to pyruvate dehydrogenase deficiency (another mitochondrial enzyme, not shown in Figure 1).

One of the most common mtDNA diseases seen is due to a single point mutation at position 3,243, with an adenine to guanine mutation in a tRNA leucine gene. Patients with this mutation may have phenotypes ranging from asymptomatic (that is, having no visible effects) to diabetes mellitus (with or without deafness). It is estimated that 1 to 2 percent of all diabetics have the A3243G mutation as the cause, affecting 200,000 people in the United States alone. The most severe phenotype to occur from this mutation has been given the acronym MELAS, for mitochondrial encephalomyopathy, with lactic acidosis and stroke-like episodes. The variability of disease phenotype or heterogeneity of disease due to mtDNA mutations arises in part because of variations in the amount of mutated mtDNA within different tissues. This mixture of wild type and mutant DNA within a cell is called heteroplasmy. In many mtDNA diseases, heteroplasmy changes over time, so that there is an increase in mutant DNA in nondividing cells and tissues such as muscle, heart, and brain, with a decrease over time in rapidly dividing tissues such as bone marrow.

Richard Haas


Johns, D. R. "Mitochondrial DNA and Disease." New England Journal of Medicine333, no. 10 (1995): 638-644.

Raha, S., and B. H. Robinson. "Mitochondria, Oxygen Free Radicals, and Apoptosis." American Journal of Medical Genetics 106, no. 1 (2001): 62-70.

Wallace, D. C. "Mitochondrial DNA in Aging and Disease." Scientific American 277, no. 2 (1997): 40-47.

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Medicine EncyclopediaGenetics in Medicine - Part 3Mitochondrial Diseases - The Importance Of The Electron Transport Chain, Mitochondrial Genes And Disease