Subfunctionalization of COX^sub 4^ paralogs in fish

Cytochrome c oxidase (COX) subunit 4 has two paralogs in most vertebrates. The mammalian COX4-2 gene is hypoxia responsive, and the protein has a disrupted ATP-binding site that confers kinetic properties on COX that distinguish it from COX4-1. The structure-function of COX4-2 orthologs in other ver...

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Bibliographic Details
Published in:American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2017-05, Vol.312 (5), p.R671
Main Authors: Porplycia, Danielle, Lau, Gigi Y, McDonald, Jared, Chen, Zhilin, Richards, Jeffrey G, Moyes, Christopher D
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Binding sites
Cardiomyocytes
Cytochrome-c oxidase
Cytochromes
Fish
Gene regulation
Heart
Heart diseases
Hypoxia
Mitochondria
Muscles
Phylogenetics
Phylogeny
Post-translation
Primates
Proteins
Rodents
Structure-function relationships
Tilapia
Transcription
Uncertainty analysis
Velocity
Ventricle
Vertebrates
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Summary:Cytochrome c oxidase (COX) subunit 4 has two paralogs in most vertebrates. The mammalian COX4-2 gene is hypoxia responsive, and the protein has a disrupted ATP-binding site that confers kinetic properties on COX that distinguish it from COX4-1. The structure-function of COX4-2 orthologs in other vertebrates remains uncertain. Phylogenetic analyses suggest the two paralogs arose in basal vertebrates, but COX4-2 orthologs diverged faster than COX4-1 orthologs. COX4-1/4-2 protein levels in tilapia tracked mRNA levels across tissues, and did not change in hypoxia, arguing against a role for differential post-translational regulation of paralogs. The heart, and to a lesser extent the brain, showed a size-dependent shift from COX4-1 to COX4-2 (transcript and protein). ATP allosterically inhibited both velocity and affinity for oxygen in COX assayed from both muscle (predominantly COX4-2) and gill (predominantly COX4-1). We saw some evidence of cellular and subcellular discrimination of COX4 paralogs in heart. In cardiac ventricle, some non-cardiomyocyte cells were COX positive but lacked detectible COX4-2. Within heart, the two proteins partitioned to different mitochondrial subpopulations. Cardiac subsarcolemmal mitochondria had mostly COX4-1 and intermyofibrillar mitochondria had mostly COX4-2. Collectively, these data argue that, despite common evolutionary origins, COX4-2 orthologs of fish show unique patterns of subfunctionalization with respect to transcriptional and posttranslation regulation relative to the rodents and primates that have been studied to date.
ISSN:0363-6119
1522-1490