More than Just Bread and Wine: Using Yeast to Understand Inherited Cytochrome Oxidase Deficiencies in Humans.

Inherited defects in cytochrome c oxidase (COX) are associated with a substantial subset of diseases adversely affecting the structure and function of the mitochondrial respiratory chain. This multi-subunit enzyme consists of 14 subunits and numerous cofactors, and it requires the function of some 30 proteins to assemble. COX assembly was first shown to be the primary defect in the majority of COX deficiencies 36 years ago. Over the last three decades, most COX assembly genes have been identified in the yeast Saccharomyces cerevisiae, and studies in yeast have proven instrumental in testing the impact of mutations identified in patients with a specific COX deficiency. The advent of accessible genome-wide sequencing capabilities has led to more patient mutations being identified, with the subsequent identification of several new COX assembly factors. However, the lack of genotype-phenotype correlations and the large number of genes involved in generating a functional COX mean that functional studies must be undertaken to assign a genetic variant as being causal. In this review, we provide a brief overview of the use of yeast as a model system and briefly compare the COX assembly process in yeast and humans. We focus primarily on the studies in yeast that have allowed us to both identify new COX assembly factors and to demonstrate the pathogenicity of a subset of the mutations that have been identified in patients with inherited defects in COX. We conclude with an overview of the areas in which studies in yeast are likely to continue to contribute to progress in understanding disease arising from inherited COX deficiencies.

Phylogenomic Analysis of 155 Helminth Species Reveals Widespread Absence of Oxygen Metabolic Capacity.

The terminal electron acceptor of most aerobic respiratory chains, cytochrome c oxidase (COX), has been highly conserved throughout evolution, from aerobic prokaryotes to complex eukaryotes. Oxygen metabolism in parasitic helminths differs significantly from that of most aerobic eukaryotes, as these organisms can switch between aerobic and anaerobic metabolisms throughout their life cycles. Early studies suggested a lack of COX activity in certain parasitic helminths, and the role of COX in helminth mitochondria remains unclear. To determine whether a functional COX is widely present in helminths, we analyzed the phylogenetic distribution of oxygen metabolism systems across 155 helminth genomes, investigating three distinct sets of protein-coding genes involved in different aspects of oxygen metabolism: COX and its assembly factors, peroxisomes, and the most abundant reactive oxygen species (ROS)-metabolizing proteins. While glycolytic and citric acid cycle enzymes are highly conserved in helminthic species, we observed an apparent widespread absence of essential COX genes across 52% of helminth species investigated. While the most common proteins involved in the defense against ROS are highly maintained across virtually all lineages, we also observed an apparent absence of essential peroxisomal protein-coding genes in 42% of species investigated. Our results suggest that a subset of parasitic helminths utilize oxygen differently from related, nonparasitic species such as Caenorhabditis elegans, with significant differences in their mitochondrial electron transport chains and peroxisomes. The identification of substantive differences between parasite and host metabolism offers a new avenue for the development of anthelmintic agents that could target these divergent pathways.