Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene

Abstract

Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Exceptions can be applied for instance to complex III-deficient patients harbouring mutations in the assembly factors BCS1L and TTC19, who showed normal complex I activity levels despite of a dramatic loss of fully-assembled complex III in different tissues (Fernandez-Vizarra et al, 2007;Ghezzi et al, 2011). Similarly, mutations in complex IV subunits or assembly factors often lead to isolated complex IV defects without complex I being affected (Tiranti et al, 1998;Zhu et al, 1998;Papadopoulou et al, 1999;Rahman et al, 1999;Valnot et al, 2000a;Valnot et al, 2000b;Antonicka et al, 2003;Massa et al, 2008). Such differences might be attributed to the nature of the mutation or the functional role of the OXPHOS mutated gene, and suggest that not all complexes III and IV structural genes are equally necessary to maintain complex I stability.…”

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

“…Both encode mt proteins (Petruzzella et al, 1998;Paret et al, 1999), which are essential for mt function as shown by the recent detection of mutations associated with fatal COX deficiencies. Mutations in hSCO2 were reported in infants who suffered from a fatal disorder with hypertrophic cardiomyopathy as the predominant symptom (Papadopoulou et al, 1999;Jaksch et al, 2000Jaksch et al, , 2001a whereas the key symptoms of the infant patients carrying mutations in the hSCO1 gene were hepatic failure and ketoacidotic coma (Valnot et al, 2000).…”

A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle

“…In addition to mutations in mitochondrial DNA-encoded COX genes 5,6 , mutations in nuclear DNA-encoded COX component genes and COX accessory factors cause COX deficiency [6][7][8] . For example, SURF1 is responsible for Leigh syndrome 9,10 , SCO1 for neonatal-onset hepatic failure and encephalopathy 11 , SCO2 for fatal infantile cardioencephalomyopathy 12 , and COX15 for fatal hypertrophic cardiomyopathy 13 . SCO1 and SCO2 are copper metallochaperones that are necessary for copper insertion into the catalytic core of COX assembly 14 .…”