Expression patterns of cytochrome c oxidase subunit 4 paralogs in relation to development and environmental challenges

Abstract

Cytochrome c oxidase (COX) is a multimeric complex of the electron transport system. The largest of the 10 nuclear-encoded subunits, subunit 4, contains two paralogs COX4-1 and COX4-2. In species studied to date (humans, rodents), COX4-1 is the more abundant paralog in all tissues, the highest expression of COX4-2 is found in brain and lung. In mammals, the two paralogs differ in hypoxia responsiveness; the COX4-2 gene is induced in response to hypoxia. The COX4-2 gene in other lower vertebrates (goldfish, zebrafish, anoles and turtles) did not appear to be hypoxia-responsive. To add to the current range of vertebrates studied, I examined the levels of COX4 transcripts and proteins in tilapia (Oreochromis niloticus) across tissues and in response to hypoxia. In contrast to mammals, (1) COX4-2 was the dominant isoform in most tissues, and (2) hypoxia did not trigger any consistent induction of the COX4-2 mRNA or protein levels. Focusing on tissues that expressed both COX4-1 and COX4-2, I used immunohistochemistry to assess the intercellular patterns of expression. In most tissues (brain, gill, and liver) the distribution of COX4-1 and COX4-2 protein appeared to be specific to individual cells, with cells expressing predominantly one paralog or the other. However, in heart, individual myocytes appeared to express both COX4 paralogs, although select non-myocytes did not express detectible COX4-2. In addition to intertissue differences in relative paralog abundance, there were transitions seen in select tissues in relation to body size. Heart, for example, was dominated by COX4-1 mRNA and protein in small fish but transitioned to predominately COX4-2 in large fish. Collectively these studies show that fish COX4-2 differs from mammalian COX4-2 in that it is generally not hypoxia responsive, but more abundant in each tissue. Whether these differences are related to metabolic regulation in relation to hypoxic metabolism remains to be demonstrated.