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Cytochrome c oxidase (COX) was initially purified more than 70 years ago. A tremendous amount of insight into its structure and function has since been gleaned from biochemical, biophysical, genetic and molecular studies. As a result, we now appreciate that COX relies on its redox-active metal centers (heme a and a 3 , Cu A and Cu B ) to reduce oxygen and pump protons in a reaction essential for most eukaryotic life. Questions persist, however, about how individual structural subunits are assembled into a functional holoenzyme. Here, we focus on what is known and what remains to be learned about the accessory proteins that facilitate Cu A site maturation. COX is a multi-subunit enzyme of dual genetic originCOX is a member of the A1 subgroup of a diverse superfamily of hemecopper oxidases. Embedded in the inner mitochondrial membrane, it is a multimeric protein complex comprised of structural subunits that are encoded by two distinct genomes. The three largest of these, COX1-3, are mitochondrially-encoded and form the catalytic core of the enzyme. COX1 contains the two heme (a, a 3 ) moieties and a mononuclear Cu B center, all of which are buried within the lipid bilayer in the fully assembled holoenzyme. COX2 harbors a mixed valence, binuclear Cu A site within a cupredoxin fold that is localized to the intermembrane space (IMS) and is solvent exposed. The Cu A site accepts electrons from cytochrome c, and subsequent electron transfer steps to the heme a and then the heme a 3 -Cu B metal centers of COX1 ultimately allow COX to convert molecular oxygen to water. Four protons are pumped across the membrane during each catalytic cycle, and contribute to the electrochemical gradient that is required for aerobic ATP production. The catalytic core is surrounded by a variable number of nuclear-encoded structural subunits (8 in yeast, 11 in humans), which function collectively to stabilize the holoenzyme, provide sites for the allosteric modulation of its catalytic activity, and facilitate its organization into higher order structures termed supercomplexes or respirasomes (reviewed in (1,2)). High resolution structures of mammalian COX (3) and of mammalian respirasomes that contain COX (8,(4) have been invaluable to advancing our understanding of how inter-subunit interactions impinge upon enzyme activity and dimerization, and the integration of COX into higher order structures.http://www.jbc.org/cgi

The purpose of this study is to determine whether benign whole body tumor volume of plexiform neurofibromas (PNs) is a risk factor for malignant peripheral nerve sheath tumors (MPNST) in individuals with neurofibromatosis type 1 (NF1). Thirty-one NF1 patients with MPNSTs and 62 age- and sex-matched NF1 patients without MPNSTs, who had undergone whole body magnetic resonance imaging (MRI) were analyzed for benign whole body tumor volume. Mann-Whitney U test, Wilcoxon signed ranks test, Fisher's exact test (two-tailed), and logistic regression analysis were used for statistical analysis. Sixteen percent of all patients with MPNST did not have internal PN. The median whole body benign tumor volume in patients with PN was 352.0 mL among the MPNST group and 3.8 mL in the comparison group (p < 0.001). When the patients were stratified by age as younger or older than 30 years (median age of MPNST diagnosis), the median benign whole body tumor volume was 693.0 mL in MPNST patients and 0.0 mL in control patients younger than 30 years (p < 0.001). The mean number of PNs in MPNST patients was 2.8 (range 0-13, median 2.0) and 1.4 (range 0-13, median 1.0) in patients without MPNST (p = 0.001). The risk of MPNST development increased 0.2 % with each additional mL of benign PN volume (adjusted odds ratio [OR] = 1.002, 95 % confidence interval [CI] 1.001-1.003, p = 0.005) and was higher in patients younger than 30 years (adjusted OR = 1.007, 95 % CI 1.002-1.012, p = 0.003). Higher numbers of PNs, larger whole body benign tumor volume, and younger age are important risk factors for MPNST. We identified a subgroup of patients with MPNST without internal PN on MRI and the lack of correlation of MPNST development with tumor burden in older patients. These findings may alter our belief that all MPNSTs arise from pre-existing PNs and suggest that surveillance MRI based on clinical suspicion may be warranted in older patients, respectively.