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

Also see Approach to the Patient With a Suspected Inherited Disorder of Metabolism.

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, severe constipation, 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 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.