The AAA⁺ ATPase ATAD3A Controls Mitochondrial Dynamics at the Interface of the Inner and Outer Membranes

Abstract

Dynamic interactions between components of the outer (OM) and inner (IM) membranes control a number of critical mitochondrial functions such as channeling of metabolites and coordinated fission and fusion. We identify here the mitochondrial AAA ؉ ATPase protein ATAD3A specific to multicellular eukaryotes as a participant in these interactions. The N-terminal domain interacts with the OM. A central transmembrane segment (TMS) anchors the protein in the IM and positions the C-terminal AAA ؉ ATPase domain in the matrix. Invalidation studies in Drosophila and in a human steroidogenic cell line showed that ATAD3A is required for normal cell growth and cholesterol channeling at contact sites. Using dominant-negative mutants, including a defective ATP-binding mutant and a truncated 50-amino-acid N-terminus mutant, we showed that ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. The capacity of ATAD3A to impact essential mitochondrial functions and organization suggests that it possesses unique properties in regulating mitochondrial dynamics and cellular functions in multicellular organisms.

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

“…We therefore performed an shRNA screen to identify downstream targets via which OmoMYC may suppress tumor cell growth. The screen identified BOP1, which is part of a trimeric complex ("PeBoW") that is essential for processing and maturation of mammalian 5.8S and 28S ribosomal RNAs 41 , ADRM1 (also known as RPN13), an ubiquitin acceptor on the proteasome 42 and ATAD3A, a calciumregulated protein involved in mitochondrial dynamics and transport from the ER to the mitochondrion 35,43 . Ribosome biogenesis and protein translation are essential for normal cell growth.…”

“…We concluded that OmoMYC regulates a group of MYC target genes that is characteristic of tumor entities expressing high levels of MYC across multiple entities. The most significant hit in this screen is ATAD3A, a protein that promotes fusion of mitochondria 35 . ATAD3A is a downstream target of the mTOR pathway and required for cell growth in Drosophila and Caenorhabditis elegans 35,36 .…”

“…The most significant hit in this screen is ATAD3A, a protein that promotes fusion of mitochondria 35 . ATAD3A is a downstream target of the mTOR pathway and required for cell growth in Drosophila and Caenorhabditis elegans 35,36 . Consistent with these observations and the screening results, shRNA-mediated depletion of ATAD3A attenuated growth of KPCs (Figure 6f,g).…”

Dynamique et morphologie mitochondriales

“…À côté des composants principaux des machineries de fusion et fission que nous venons de décrire, et qui sont globalement conservés de la levure à l'homme, d'autres acteurs de la dynamique mitochondriale, qui sont souvent spécifiques aux levures ou aux mammifères, ont également été identifiés [4]. Par exemple, chez les mammifères, la protéine de fission GDAP1 (gangliosideinduced differentiation-associated protein 1), responsable d'une neuropathie chez l'homme (➜) et ATAD3A (ATPase family, AAA domain containing 3A), qui joue un rôle dans l'établissement et/ ou la régulation des interactions entre les membranes externe et interne [18]. Chez la levure, les protéines Mdm10, Mdm12 et Mmm1, identifiées originellement comme des protéines de tubulation, viennent d'être impliquées dans l'interaction entre les mitochondries et le réticulum endoplasmique [19].…”

ATAD3, une ATPase membranaire mitochondriale vitale impliquée dans la progression tumorale

“…< des études lui reconnaissent un rôle important. En effet, son expression est ubiquitaire, et elle est essentielle à l'embryogenèse, à la structuration du réseau mitochondrial et aux interactions fonctionnelles entre mitochondries et réticulum endoplasmique [4][5][6][7]. ATAD3 participe donc à une fonction mitochondriale vitale qui reste à découvrir.…”