Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

Abstract

Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.

Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes

“…7A). Remarkably, previous studies had evidenced that resveratrol, an anti-oxidant metabolite, improves complex IV activity [43], thus strengthening our results. In addition, Blue Native (BN)-PAGE analyses of digitonin-solubilized adipocyte mitochondria revealed that complex IV was found significantly decreased in diabetic compared to non-diabetic patients (Fig.…”

“…The occurrence of shared features between aging and T2DM explains that 37% of DAPs were found common to the two comparisons. Thus, cytochrome c oxidase subunit 6B1 (COX6B1), a key player in cytochrome c oxidase activity [43], [44], was found down-regulated in the age (Zq=−2.75) and T2DM (Zq=−5.06) comparisons.…”

“…This minor pathway depends on redox-regulated folding events that stabilize, trap and finally import into the mitochondrion the C-X 9 -C domain-carrying proteins like NDUFA8, NDUFS5 and COX6B1. NDUFA8, NDUFS5 are important accessory molecules that take part in the last stages of complex I assembly [68], whereas COX6B1 is a key protein involved in the biogenesis [69] and the stabilization of complex IV subunits [43]. Noteworthy, our redox proteomics data revealed that in T2DM comparison Cys-peptides from the aforementioned C-X 9 -C domain-carrying proteins were significantly oxidized; likewise, in the aging comparison several oxCys-containing peptides from COX6B1 were significantly increased (Table 2).…”

Maintaining Ancient Organelles

“…51 Finally, mutations in CIII and CIV have been shown to result in human patients with cardiomyopathy. 52–55 …”

Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts

“…For diagnostic testing, cultured skin fibroblasts are an attractive tissue to evaluate OXPHOS function because of the minimally invasive character of sampling and the amount of cell material obtained by culturing [7]. Studies in human COX-deficient fibroblasts, derived from patients, have revealed diminished COX activity, compromised ATP production, reactive oxygen species (ROS) overproduction and abnormal mitochondrial morphology [8–10]. …”