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Mitochondrial Oxidative Phosphorylation Disorders


Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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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 adenosine triphosphate (ATP). Defects involving enzymes used in this process impair cellular respiration, decreasing the ATP:ADP (adenosine diphosphate) ratio. Mitochondria have their own DNA (mitochondrial DNA [mtDNA]), which is maternally derived. However, mtDNA shares responsibility with nuclear DNA for mitochondrial function. Thus, both mitochondrial and nuclear mutations can cause mitochondrial disorders.

Tissues with a high energy demand (eg, brain, nerves, retina, skeletal and cardiac muscle) are particularly vulnerable to defects in oxidative phosphorylation.

The most common clinical manifestations are

  • Seizures

  • Hypotonia

  • Ophthalmoplegia

  • Strokelike episodes

  • Muscle weakness

  • Severe constipation

  • 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 Pyruvate Metabolism Disorders Inability to metabolize pyruvate causes lactic acidosis and a variety of central nervous system abnormalities. Pyruvate is an important substrate in carbohydrate metabolism. Pyruvate metabolism... read more , 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 disease, Alzheimer disease, diabetes, deafness, cancer).

The following disorders are conditions with a known phenotype/genotype correlation. Other less well-defined defects in mitochondrial function exist. Additionally, there are a number of conditions in which a genetic defect causes secondary mitochondrial dysfunction.

Leber 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 mitochondrial DNA 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 that involve mutations of mtDNA.

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

Mutations in the mitochondrial tRNAleu gene cause this progressive neurodegenerative disease characterized by repeated episodes of “chemical (metabolic) 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 tRNAlys 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 years.

Kearns-Sayre syndrome is caused by a large contiguous deletion in mtDNA that results in the loss of genes important for mitochondrial protein formation and oxidative phosphorylation.

CPEO can result from mutations in one of several different nuclear genes that are critical for the production and maintenance of mtDNA and result in the deletion of large segments of mtDNA in muscle cells. Less common causes involve point mutations in mtDNA genes that provide instructions for making molecules called transfer RNAs.

Neuropathy, ataxia, and retinitis pigmentosa (NARP)

NARP is a progressive condition characterized by sensory neuropathy (with numbness, tingling or pain in the extremities), muscle weakness, ataxia, vision loss caused by retinal deterioration (retinitis pigmentosa Retinitis Pigmentosa Retinitis pigmentosa is a slowly progressive, bilateral degeneration of the retina and retinal pigment epithelium caused by various genetic mutations. Symptoms include night blindness and loss... read more Retinitis Pigmentosa ), cognitive decline, seizures, hearing loss, and cardiac conduction defects. The disorder can begin in childhood or early adulthood.

NARP results from mutations in the ATP6 gene contained in mtDNA. ATP6 mutations alter the structure or function of adenosine triphosphate (ATP) synthase, reducing the ability of mitochondria to make ATP.

Leigh disease (subacute necrotizing encephalopathy)

Leigh disease is a severe neurologic disorder that usually manifests in the first year of life. It is characterized by progressive swallowing problems, poor weight gain, hypotonia, weakness, ataxia, ophthalmoplegia, nystagmus, and optic atrophy along with lactic acidosis. Patients typically die within 2 to 3 years, usually due to respiratory failure.

Imaging studies show degenerative lesions in the basal ganglia, cerebellum, and brain stem.

Leigh disease results from mutations in one of more than 75 different nuclear or mtDNA genes involved in energy production in mitochondria.

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