Abstract
The biogenesis and function of eukaryotic cytochrome c oxidase or mitochondrial respiratory chain complex IV (CIV) undergo several levels of regulation to adapt to changing environmental conditions. Adaptation to hypoxia and oxidative stress involves CIV subunit isoform switch, changes in phosphorylation status, and modulation of CIV assembly and enzymatic activity by interacting factors. The latter include the Hypoxia Inducible Gene Domain (HIGD) family yeast respiratory supercomplex factors 1 and 2 (Rcf1 and Rcf2) and two mammalian homologs of Rcf1, the proteins HIGD1A and HIGD2A. Whereas Rcf1 and Rcf2 are expressed constitutively, expression of HIGD1A and HIGD2A is induced under stress conditions, such as hypoxia and/or low glucose levels. In both systems, the HIGD proteins localize in the mitochondrial inner membrane and play a role in the biogenesis of CIV as a free unit or as part as respiratory supercomplexes. Notably, they remain bound to assembled CIV and, by modulating its activity, regulate cellular respiration. Here, we will describe the current knowledge regarding the specific and overlapping roles of the several HIGD proteins in physiological and stress conditions.
Highlights
Mitochondrial cytochrome c oxidase (COX) or respiratory chain complex IV (CIV) is the primary site of cellular oxygen consumption and essential for aerobic energy generation in the chemical form of ATP [1]
Mitochondrial cytochrome c oxidase is a copper-heme A oxidase formed by three conserved catalytic core membrane subunits (COX1, COX2, and COX3) encoded in the mitochondrial DNA
The encoded proteins were shown to co-migrate with CIV in a large-scale proteomic analysis of mitochondrial extracts resolved by Blue Native (BN)-PAGE [49]
Summary
Mitochondrial cytochrome c oxidase (COX) or respiratory chain complex IV (CIV) is the primary site of cellular oxygen consumption and essential for aerobic energy generation in the chemical form of ATP [1]. Whereas the catalytic core is conserved in the bacterial enzyme, the addition of supernumerary subunits occurred sequentially during evolution as an adaptation to cope with evolving oxygen-rich atmosphere and eukaryotic cell energetic requirements and to regulate CIV activity and cellular respiration [3] Some of these CIV subunits exist in several isoforms that are tissue-specific in mammals or preferentially expressed under stress [4,5,6,7]. The graph was generated with tools from pfam.xfam.org hosted by the European Bioinformatics Institute at the European Molecular Biology visualization of the taxonomic lineage distribution of 1911 different species that in total have 3472 protein sequences containing the hypoxia-inducible gene (HIG)-1-N domain (Pfam ID: PF04588). We will briefly summarize our current understanding of the mechanisms by which HIGD proteins control CIV biogenesis and will detail how these proteins regulate CIV activity and cellular respiration in yeast and mammals in physiological, stress, and disease conditions
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