ATCO1, a mitochondrial master regulator of ATP synthase and cytochrome oxidase biogenesis?

Abstract

Fungal and mammalian ATP Synthase and Cytochrome C oxidase (COX) are examples of mitochondrial hetero-oligomeric complexes whose assembly depends on the expression of mitochondrial and nuclear genes. In prior studies, yeast ATP synthase was shown to be assembled from three modules, each formed by a separate pathway. The simplest module is a ring, which in yeast consists of 10 identical copies of mitochondrially encoded Atp9 (homolog of bacterial C subunit). The ring is an important structural and functional component of the rotor in F-, V- and A- type ATPases and functions to either use a proton gradient to form the phosphodiester bond of ATP or hydrolyze ATP to generate a proton gradient. Nascent Atp9, not yet assembled into the ring, was recently found to be physically associated with Cox6 (subunit of COX encoded by the nuclear DNA) in high molecular weight complexes named ATCO1 (ATP synthase and COX). Our experiments indicate that ATCO1 is a source of Atp9 for ATP synthase assembly. This evidence provides the basis for the hypothesis that one of the functions of ATCO1 is to confer an adequate stoichiometry of ATP synthase and COX for their function in oxidative phosphorylation. The main objective of this project is to verify experimentally the role of ATCO1 in coordinating assembly of ATP synthase and COX. We will also determine if ATCO1 is present in human mitochondria. The studies on the novel ATCO1 complex will increase our understanding of how the mitochondrial respiratory chain is assembled and how this process is regulated. (AU)