Mitochondrial disorders are also known as or subsume Respiratory chain defects. -ed.
Mitochondrial myopathies were described in the early 1960s, when systematic ultrastructural and histochemical studies revealed excessive proliferation of normal- or abnormal-looking mitochondria in muscle of patients with weakness or exercise intolerance (Shy and Gonatas 1964; Shy et al 1966). Because, with the modified Gomori trichrome stain, the areas of mitochondrial accumulation appeared crimson, the abnormal fibers were dubbed “ragged-red fibers” (Engel and Cunningham 1963) and came to be considered the pathological hallmark of mitochondrial disease. However, it soon became apparent that in many patients with ragged-red fibers, the myopathy is associated with symptoms and signs of brain involvement, and the term “mitochondrial encephalomyopathies” was introduced. It also became clear that lack of ragged-red fibers in the biopsy does not exclude a mitochondrial etiology, as exemplified by Leigh syndrome, an encephalopathy of infancy or childhood invariably due to mitochondrial dysfunction but rarely accompanied by ragged-red fibers.
According to the widely accepted “endosymbiotic hypothesis,” mitochondria are the relics of protobacteria that populated anaerobic nucleated cells and endowed them with the precious gift of oxidative metabolism. Thus, mitochondria are the main source of energy for all human tissues and contain many metabolic pathways, including the pyruvate dehydrogenase complex, the carnitine cycle, the beta-oxidation “spirals,” and the Krebs cycle (also known as “tricarboxylic acid cycle”).
Although defects in all of these pathways are, by definition, mitochondrial diseases, the term “mitochondrial encephalomyopathy” has come to indicate disorders due to defects in the respiratory chain (DiMauro and Schon 2003; DiMauro et al 2013). This is the “business end” of oxidative metabolism, where ATP is generated. Reducing equivalents produced in the Krebs cycle and in the beta-oxidation spirals are passed along a series of protein complexes embedded in the inner mitochondrial membrane (the electron transport chain). The electron transport chain consists of 4 multimeric complexes (I to IV) plus 2 small electron carriers, coenzyme Q10 (or ubiquinone) and cytochrome c. The energy generated by these reactions is used to pump protons from the mitochondrial matrix into the space between the inner and outer mitochondrial membranes. This creates an electrochemical proton gradient, which is utilized by complex V (or ATP synthase) to produce ATP in a process known as oxidation/phosphorylation coupling.
A unique feature of the respiratory chain is its dual genetic control: mitochondrial DNA (mtDNA) encodes 13 of the approximately 80 proteins that compose the respiratory chain, and nuclear DNA (nDNA) encodes all the others. Notably, complex II, coenzyme Q10, and cytochrome c are exclusively encoded by nDNA. In contrast, complexes I, III, IV, and V contain some subunits encoded by mtDNA: 7 for complex I (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6), 1 for complex III (cytochrome b), 3 for complex IV (COX I, COX II, and COX III), and 2 for complex V (ATPase 6 and ATPase 8) (DiMauro and Schon 2003; DiMauro et al 2013).
Human mtDNA is a 16,569-kb circular, double-stranded molecule, which contains 37 genes: 2 rRNA genes, 22 tRNA genes, and 13 structural genes encoding the respiratory chain subunits listed above. In the course of evolution, mtDNA has lost much of its original autonomy and now depends heavily on the nuclear genome for the production of factors needed for mtDNA transcription, translation, and replication. In the course of evolution, mtDNA has lost much of its original autonomy and now depends heavily on the nuclear genome for the production of factors needed for mtDNA integrity; transcription, translation, and replication (“maintenance”); inner membrane integrity; and mitochondrial dynamics (DiMauro et al 2013).
Since 1988, the circle of mtDNA has become crowded with pathogenic mutations, and the principles of mitochondrial genetics should, therefore, be familiar to the practicing physician.
Heteroplasmy and threshold effect. Each cell contains hundreds or thousands of mtDNA copies, which, at cell division, distribute randomly among daughter cells. In normal tissues, all mtDNA molecules are identical (homoplasmy). Deleterious mutations of mtDNA usually (but not always) affect only some but not all mtDNAs. The clinical expression of a pathogenic mtDNA mutation is largely determined by the relative proportion of normal and mutant genomes in different tissues. A minimum critical number of mutant mtDNAs is required to cause mitochondrial dysfunction in a particular organ or tissue and mitochondrial disease in an individual (threshold effect).
Mitotic segregation. At cell division, the proportion of mutant mtDNAs in daughter cells may shift, and the phenotype may change accordingly. This phenomenon, called “mitotic segregation,” explains how the clinical phenotype may change in certain patients with mtDNA-related disorders, as they grow older.
Maternal inheritance. At fertilization, all mtDNA derives from the oocyte. Therefore, the mode of transmission of mtDNA and of mtDNA point mutations (single deletions of mtDNA are usually sporadic events) differs from Mendelian inheritance. A mother carrying an mtDNA point mutation will pass it on to all of her children (boys and girls), but only her daughters will transmit it to their progeny.
The best way for a clinician to chart a course toward a diagnosis in the morass of mitochondrial encephalomyopathies is to use a classification that combines clinical features, muscle histochemistry and biochemistry, and genetics. From the genetic point of view, there are 2 major categories: disorders due to defects of mtDNA and disorders due to defects of nDNA (see Table 1).
Table 1. Mitochondrial Disorders by Genetic Defect
Mutations in mtDNA
Mutations in nDNA