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Mitochondrial Oxidative Phosphorylation Disorders

by Chin-To Fong, MD

Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the CNS, retina, and muscle.

Cellular respiration (oxidative phosphorylation) occurs in the mitochondria, where a series of enzymes catalyze the transfer of electrons to molecular oxygen and the generation of energy-storing ATP. Mitochondrial or nuclear genetic defects involving enzymes used in this process impair cellular respiration, decreasing the ATP:ADP ratio. Tissues with a high energy demand (eg, brain, nerves, retina, skeletal and cardiac muscle) are particularly vulnerable. The most common clinical manifestations are seizures, hypotonia, ophthalmoplegia, strokelike episodes, muscle weakness, and cardiomyopathy.

Biochemically, there is profound lactic acidosis because the NADH:NAD ratio increases, shifting the equilibrium of the lactate dehydrogenase reaction toward lactate. The increase in the lactate:pyruvate ratio distinguishes oxidative phosphorylation defects from other genetic causes of lactic acidosis such as pyruvate carboxylase or pyruvate dehydrogenase deficiency, in which the lactate:pyruvate ratio remains normal. A large number of oxidative phosphorylation defects have been described; only the most common ones are outlined here, along with their distinguishing features.

Mitochondrial mutations and variants have also been implicated in a number of diseases of aging (eg, Parkinson’s disease, Alzheimer’s disease, diabetes, deafness, cancer).

Leber’s hereditary optic neuropathy (LHON)

This disease is characterized by acute or subacute bilateral central vision loss caused by retinal degeneration. Onset usually occurs in the patient’s 20s or 30s but can occur from childhood to adulthood. Male:female ratio is 4:1. Many mutations have been defined, but 3 common ones account for 90% of those in European patients. LHON pedigrees usually show a pattern of maternal inheritance typical of mitochondrial disorders.

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)

Mutations in the mitochondrial tRNA leu gene cause this progressive neurodegenerative disease characterized by repeated episodes of “chemical strokes,” myopathy, and lactic acidosis. In many cases, cells contain both wild-type and mutant mitochondrial DNA (heteroplasmy); thus, expression is variable.

Myoclonic epilepsy with ragged-red fibers (MERRF)

This progressive disorder is characterized by uncontrolled muscle contractions (myoclonic seizures), dementia, ataxia, and myopathy, which shows ragged-red fibers (indicating mitochondrial proliferation) with specialized stains when biopsied. Mutations are in the mitochondrial tRNA lys gene. Heteroplasmy is common; thus, expression is variable.

Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO)

These disorders are characterized by ophthalmoplegia, ptosis, atypical retinitis pigmentosa, ragged-red fiber myopathy, ataxia, deafness, and cardiomyopathy typically occurring before age 20 yr. Most mutations involve contiguous deletion/duplication of part of the mitochondrial transfer RNA and other protein-coding genes.

Neurogenic muscle atrophy and retinitis pigmentosa (NARP) and Leigh disease

Pigmentary retinopathy in the presence of neuromuscular degeneration and Leigh disease (subacute necrotizing encephalopathy characterized by ataxias and basal ganglia degeneration) is a genetically heterogeneous syndrome. Mutations can be seen in the ATP6 gene of the mitochondrial genomes.

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