Mutations in COX15 Produce a Defect in the Mitochondrial Heme Biosynthetic Pathway, Causing Early-Onset Fatal Hypertrophic Cardiomyopathy

Abstract

Deficiencies in the activity of cytochrome c oxidase (COX), the terminal enzyme in the respiratory chain, are a frequent cause of autosomal recessive mitochondrial disease in infants. These patients are clinically and genetically heterogeneous, and all defects so far identified in this group have been found in genes coding for accessory proteins that play important roles in the assembly of the COX holoenzyme complex. Many patients, however, remain without a molecular diagnosis. We have used a panel of retroviral vectors expressing human COX assembly factors in these patients to identify the molecular basis for the COX deficiency by functional complementation. Here we show that overexpression of COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, can functionally complement the isolated COX deficiency in fibroblasts from a patient with fatal, infantile hypertrophic cardiomyopathy. Mutation analysis of COX15 in the patient identified a missense mutation (C700T) on one allele, changing a conserved arginine to tryptophan (R217W), and a splice-site mutation in intron 3 on the other allele (C447-3G), resulting in a deletion of exon 4. This splicing error introduces a frameshift and a premature stop codon, resulting in an unstable mRNA and, likely, a null allele. Mitochondrial heme A content was reduced in the patient's heart and fibroblast mitochondria, and levels of heme O were increased in the patient's heart. COX activity and the total amount of fully assembled enzyme were reduced by 50%-70% in patient fibroblasts. Expression of COX15 increased heme A content and rescued COX activity. These results suggest that reduced availability of heme A stalls the assembly of COX. This study establishes COX15 as an additional cause, along with SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated COX deficiency.

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.…”

Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis

“…The ferredoxin electron transfer chains are of considerable medical importance. A genetic defect in human Cox15 leads to infantile COX deficiency and cardiomyopathy, AdR has been shown to act as a tumor suppressor, and defects in CYPs are associated with several diseases (17)(18)(19).…”

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 .…”