Atad3 Function Is Essential for Early Post-Implantation Development in the Mouse

Tobias Goller,Ursula K Seibold,Elisabeth Kremmer,Waldemar Kolanus,Wolfgang Voos,Jennifer Nichols

doi:10.1371/journal.pone.0054799

Tobias Goller, Ursula K Seibold + Show 4 more

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https://doi.org/10.1371/journal.pone.0054799

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Journal: PloS one	Publication Date: Jan 25, 2013
Citations: 43	License type: CC BY 4.0

Affiliation: University of Bonn, Helmholtz Zentrum München

Abstract

The mitochondrial AAA+-ATPase ATAD3 is implicated in the regulation of mitochondrial and ER dynamics and was shown to be necessary for larval development in Caenorhabditis elegans. In order to elucidate the relevance of ATAD3 for mammalian development, the phenotype of an Atad3 deficient mouse line was analyzed. Atad3 deficient embryos die around embryonic day E7.5 due to growth retardation and a defective development of the trophoblast lineage immediately after implantation into the uterus. This indicates an essential function of Atad3 for the progression of the first steps of post-implantation development at a time point when mitochondrial biogenesis and ATP production by oxidative phosphorylation are required. Therefore, murine Atad3 plays an important role in the biogenesis of mitochondria in trophoblast stem cells and in differentiating trophoblasts. At the biochemical level, we report here that ATAD3 is present in five native mitochondrial protein complexes of different sizes, indicating complex roles of the protein in mitochondrial architecture and function.

Highlights

ATAD3 belongs to the ancient family of AAA+-ATPases (ATPases associated with a wide variety of cellular activities) [1]
Previous studies in human cell lines and in Caenorhabditis elegans showed that ATAD3 AAA+-ATPases are localized to mitochondria, where they probably are arranged in oligomers that span both mitochondrial membranes with the enzymatic domain positioned in the matrix [2,7,19]
It is proposed that ATAD3 is implicated in the regulation of mitochondrial and endoplasmatic reticulum (ER) dynamics, as interactions with mitochondrial fission (DRP1) and fusion proteins could be proofed [2,6,7,19]

Summary

Introduction

ATAD3 belongs to the ancient family of AAA+-ATPases (ATPases associated with a wide variety of cellular activities) [1]. The protein structure of ATAD3 is characterized by two Nterminal coiled-coil domains, a central trans-membrane segment and a conserved C-terminal ATPase domain of the AAA+-type with an ATP-binding (Walker A motif) and a catalytic ATPase domain (Walker B motif) [2]. AAA+-ATPases are proposed to be chaperones or proteases and are involved in a variety of cellular processes e.g. cell cycle regulation, biogenesis of cell organelles and dis/assembly of protein complexes [3,4,5]. Analysis of ATAD3A topology in mitochondria by employing trypsin digestion experiments showed that the Cterminal AAA+-ATPase domain is located in the matrix, whereas a central trans-membrane segment anchors the protein in the inner membrane. The N-terminal domain interacts with the outer membrane [2]. An oligomerization of ATAD3A monomers has been proposed [2] which is supported by findings showing that other AAA+-proteins are assembling as hexameric rings [4,9,10]

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