Cytochrome c oxidase deficiency

Abstract

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain, catalyzing the transfer of electrons from reduced cytochrome c to molecular oxygen. It is composed of 13 structural subunits, three of which are encoded in mtDNA and form the catalytic core of the enzyme. In addition to these structural subunits, a large number of accessory factors are necessary for the assembly and maintenance of the active holoenzyme complex. Most isolated COX deficiencies are inherited as autosomal recessive disorders; mutations in the mtDNA-encoded COX subunit genes are relatively rare. These mutations are associated with a wide spectrum of clinical phenotypes ranging from isolated myopathy to multisystem disease, with onset from late childhood to adulthood. Autosomal recessive COX deficiencies generally have a very early age of onset and a fatal outcome. Several clinical presentations have been described including Leigh Syndrome, hypertrophic cardiomyopathy and myopathy, and fatal infantile lactic acidosis. Surprisingly, mutations in the nuclear-encoded structural COX subunits have not been found in association with any of these phenotypes. Mutations have, however, been identified in several COX assembly factors: SURF1 (Leigh Syndrome), SCO2 (hypertrophic cardiomyopathy), SCO1 (hepatic failure, ketoacidotic coma), and COX10 (encephalopathy, tubulopathy). As all of these assembly factors are ubiquitously expressed, the molecular basis for the different clinical presentations remains unexplained. Although the genetic defects in the majority of patients with COX deficiency are unknown, it is likely that most will be solved in the near future using functional complementation techniques.

Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of Cu A in human cytochrome oxidase

“…Assembly of the oxidase is a complex process involving the synthesis and folding of the individual subunits and the incorporation of the metal cofactors (10). For the human oxidase, at least seven genes encoding for different proteins are required for maturation of these two copper sites (11)(12)(13)(14)(15)(16)(17).…”

Mitochondrial Disease in Childhood: Nuclear Encoded

“…These disorders are also quite common, being responsible for 25 % of all pediatric mitochondrial disease; Leigh syndrome is the most common clinical manifestation [43]. These disorders have included clinical manifestations of neonatal-onset hepatic failure (SCO1), cardioencephalomyopathy (SCO2), hypertrophic cardiomyopathy (COX15), and encephalomyopathy (COX6B1) [44].…”

Hereditary optic neuropathies

“…1,2,188 This disorder may be inherited in an autosomal recessive, X-linked, or maternal pattern, depending on the genetic defect. The onset of symptoms is typically between the ages of 2 months and 6 years, and consists of progressive deterioration of brainstem functions, ataxia, seizures, peripheral neuropathy, intellectual deterioration, impaired hearing and poor vision.…”