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Progressive multiorgan disease. The mitochondrial
myopathies are a rare group of conditions affecting the respiratory chain
and oxidative phosphorylation. A total of five proteins complexes make up
the mitochondrial electron transport chain (see Complex Diseases/Deficiency (Overview)).
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Mitochondria are the main source of adenosine tri-phosphate (ATP)
in the cell. They depend on several metabolic pathways to supply ATP during
varying cellular conditions: glycolysis is the main pathway during
nutritional repletion state, and fatty acid oxidation is the main pathway
during fasting. ATP is generated by five protein complexes, called the respiratory chain, contained in the inner mitochondrial membrane: NADH from
the tricarboxylic cycle is a substrate for complex I, and the reduced form of
flavin adenine dinucleotide (FADH2) from fatty acid oxidation is a
substrate for complex II. Strictly speaking, disorders of pyruvate
metabolism, fatty acid oxidation, ketogenesis, or ketolysis, and defects of
the urea cycle or of the respiratory chain, are mitochondrial pathologies;
however, the term mitochondrial diseases is usually a synonym for
respiratory chain or oxidative phosphorylation anomaly.
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Mitochondrial Cytopathy; Mitochondrial Myopathy
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In the United States, it is estimated that one in 4,000
children will develop mitochondrial disease by the age of 10 years. The
prevalence of the disease at birth is 1:4000 to have a type of mitochondrial
disease.
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Any mode of inheritance may be observed:
autosomal recessive, dominant, X-linked, maternal, or sporadic. This is a
consequence of the high number of genes encoding respiratory chain proteins:
most are located in the cell DNA but 26 are in the mtDNA. Consequently,
mutations, depletion, deletions, or duplications can occur in both genetic
materials. Transmission of mitochondrial diseases is complex because mtDNA
is maternally inherited, has a different structure than complementary DNA,
and is more subject to spontaneous mutations. Therefore, many mtDNA
mutations accumulate with age and are probably the cause of some diseases
(e.g., Parkinson, diabetes). Moreover, there are many mitochondria in each
cell, and they are randomly partitioned between daughter cells during
mitosis. Thus, if normal and mutant mtDNA are present in the initial cell
(heteroplasmy), some lineages will have only abnormal mtDNA or normal mtDNA
(homoplasmy). There are also cases of acquired reversible mitochondrial
dysfunction caused by mtDNA depletion in children with HIV treated with nucleoside analogues (mainly zidovudine [AZT]); AZT
inhibits DNA polymerase γ, a nuclear protein essential for mtDNA
replication and maintenance.
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Whether cells can generate enough ATP depends on
the amount of dysfunctional mtDNA present in the mitochondria. Because cells
of different organs have different metabolic needs, some organs can tolerate
a greater burden of mutated mtDNA, and the first symptoms usually appear in
the organs with the greatest metabolic needs (e.g., brain, heart, muscle,
liver, kidney). This is called the threshold effect. The concepts of heteroplasmy and
threshold effect explain how the same mutation can present with many
different phenotypes and how some clinical phenotypes are caused by
different mutations. If the ...