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  • Typically multisystemic disorders predominantly affecting brain and skeletal muscle (encephalomyopathies)

  • Lactic acid often increased in blood, cerebrospinal fluid (CSF), or both

  • Biochemical defects in the mitochondrial oxidative phosphorylation (OXPHOS) pathway

General Considerations

Mitochondria are essential cellular organelles that convert metabolites of carbohydrates, lipids, and proteins into a usable form of energy—adenosine triphosphate (ATP). By convention, the term mitochondrial diseases refers to disorders caused by defects in OXPHOS, the terminal mitochondrial pathway responsible for generating ATP.

In mammals, OXPHOS enzymes are unique because they are the products of two genomes—nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). The dual genetic origin of the respiratory chain contributes to the clinical heterogeneity of mitochondrial diseases. Because of their phenotypic diversity and complex multisystemic presentations, mitochondrial diseases can be difficult to diagnose. Most often, mitochondrial diseases affect brain and skeletal muscle and are therefore called mitochondrial encephalomyopathies (Table 24–1). Central nervous system manifestations of mitochondrial diseases include dementia, strokes at a young age, seizures, myoclonus, migraine-like headaches, optic neuropathy, and hearing loss. Myopathic involvement often presents as ptosis and progressive ophthalmoparesis, oropharyngeal weakness, exercise intolerance, and limb myopathy. Endocrinopathies and cardiopathies are common in mitochondrial diseases. Gastrointestinal, hematologic, renal, and psychiatric manifestations are also observed.

Table 24–1.Typical features of mitochondrial diseases.

A. Biochemical Functions of Mitochondria

Mitochondria perform multiple vital biochemical functions, including breakdown of fatty acids through β-oxidation and catabolism of pyruvate derived from glycogen via the Krebs or citric acid cycle (Figure 24–1). These two metabolic pathways liberate electrons that are transported through four respiratory chain enzymes (complexes I–IV) embedded within the inner membrane of mitochondria. The transport of electrons through these enzyme complexes generates, across the inner membrane, a proton gradient that drives the synthesis of ATP at complex V (oxidation-phosphorylation).

Figure 24–1.

Schematic representation of mitochondrial metabolism. Respiratory chain components or complexes encoded by nuclear DNA are white ovals; subunits encoded by mitochondrial DNA are gray rectangles. ADP = adenosine diphosphate; ATP = adenosine triphosphate; CoA = coenzyme A; CoQ = coenzyme Q; Cyt b and c = cytochrome b and c; FADH2 = flavin adenine dinucleotide (reduced form); NADH = nicotinamide adenine dinucleotide (reduced form); PDC = pyruvate dehydrogenase complex; I, II, III, IV, V = oxidative phosphorylation complexes.

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