Clinical Pathology: General Principles, Lab Management, Clinical Chemistry, Immunology & Histocompatibility, Genetic Testing

• The mitochondrial respiratory chain is composed of about 75 multiprotein subunits organized in five separate complexes embedded in the inner mitochondrial membrane. Thirteen of these subunits are encoded by mitochondrial DNA (mtDNA): seven in complex I, one in complex III, three in complex IV, and two in adenosine triphosphate (ATP) synthase or complex V.

• Human mtDNA is a 16-kb circular, double-stranded molecule, that contains 37 genes: 2 rRNA, 22 tRNA, and 13 structural genes encoding subunits of the mitochondrial respiratory chain.

• All eukaryotic cells contain many copies of mtDNA, which, at division, distribute randomly among daughter cells. In normal tissues, all copies of mtDNA are identical (homoplasmy). Disease-causing mutations usually affect some, but not all, mtDNA. Therefore, in this case, cells and tissues harbor both wild-type and mutant mtDNA, a condition known as heteroplasmy. A minimal amount of mutant mtDNA must be present before there is a manifestation of respiratory dysfunction and appearance of clinical symptoms; this is known as the threshold effect.

• The threshold in tissues such as brain, muscle, heart, and endocrine glands with high oxidative energy demand is low compared with other tissues. Therefore, these tissues are especially vulnerable to respiratory chain dysfunction.

• Because mitochondria are randomly distributed at cell division, the proportion of mutant and wild-type mtDNA in daughter cells may change, and the phenotype may change accordingly. This phenomenon, called mitotic segregation, explains the age-related variability of clinical features frequently observed in mtDNA-related disorders.

Lehninger A, Nelson D, Cox M: Principles of Biochemistry. 2nd ed. New York: World Publishers; 1993.

DiMauro S, Schon E: Mitochondrial respiratory-chain diseases.N Engl J Med 2003;348:2656–2668.

DiMauro S, Hirano M: Pathogenesis and treatment of mitochondrial disorders.Adv Exp Med Biol 2009;652:139–170.

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