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

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2010 Feb 16

PMID 20154147

Citations 74

Authors

Benoit Gilquin

Emmanuel Taillebourg

Nadia Cherradi

Arnaud Hubstenberger

Olivia Gay

Nicolas Merle

Nicole Assard

Marie-Odile Fauvarque

Shiho Tomohiro

Osamu Kuge

Jacques Baudier

Affiliations

Soon will be listed here.

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.

Citing Articles

Thirty years of StAR gazing. Expanding the universe of the steroidogenic acute regulatory protein.

Miller W, Miller W J Endocrinol. 2025; 264(3).

PMID: 39773408 PMC: 11840834. DOI: 10.1530/JOE-24-0310.

Mutations in mitochondrial gene and disease, lessons from models.

Brugel M, Kiesel A, Haack T, Peralta S Front Neurosci. 2024; 18:1496142.

PMID: 39605788 PMC: 11599198. DOI: 10.3389/fnins.2024.1496142.

Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies.

He Y, Liu Y, Zheng M, Zou Y, Huang M, Wang L Adv Sci (Weinh). 2024; 12(1):e2404109.

PMID: 39520088 PMC: 11714148. DOI: 10.1002/advs.202404109.

AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.

Li M, Wang Y, Wei X, Cai W, Wu J, Zhu M Cell Res. 2024; 34(10):683-706.

PMID: 38898113 PMC: 11442470. DOI: 10.1038/s41422-024-00985-6.

Knockdown of hCINAP sensitizes colorectal cancer cells to ionizing radiation.

Shen M, Zhang Y, Wu F, Shen M, Zhang S, Guo Y Cell Cycle. 2024; 23(3):233-247.

PMID: 38551450 PMC: 11057657. DOI: 10.1080/15384101.2024.2309015.

References

Jefcoate C . High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex. J Clin Invest. 2002; 110(7):881-90. PMC: 151162. DOI: 10.1172/JCI16771. View

Grandemange S, Herzig S, Martinou J . Mitochondrial dynamics and cancer. Semin Cancer Biol. 2009; 19(1):50-6. DOI: 10.1016/j.semcancer.2008.12.001. View

Hubstenberger A, Labourdette G, Baudier J, Rousseau D . ATAD 3A and ATAD 3B are distal 1p-located genes differentially expressed in human glioma cell lines and present in vitro anti-oncogenic and chemoresistant properties. Exp Cell Res. 2008; 314(15):2870-83. DOI: 10.1016/j.yexcr.2008.06.017. View

Bird I, Hanley N, Word R, Mathis J, McCARTHY J, Mason J . Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive aldosterone secretion. Endocrinology. 1993; 133(4):1555-61. DOI: 10.1210/endo.133.4.8404594. View

Dietzl G, Chen D, Schnorrer F, Su K, Barinova Y, Fellner M . A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature. 2007; 448(7150):151-6. DOI: 10.1038/nature05954. View

DeVay R, Dominguez-Ramirez L, Lackner L, Hoppins S, Stahlberg H, Nunnari J . Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. J Cell Biol. 2009; 186(6):793-803. PMC: 2753158. DOI: 10.1083/jcb.200906098. View

Pon L, Moll T, Vestweber D, Marshallsay B, Schatz G . Protein import into mitochondria: ATP-dependent protein translocation activity in a submitochondrial fraction enriched in membrane contact sites and specific proteins. J Cell Biol. 1989; 109(6 Pt 1):2603-16. PMC: 2115932. DOI: 10.1083/jcb.109.6.2603. View

Rone M, Fan J, Papadopoulos V . Cholesterol transport in steroid biosynthesis: role of protein-protein interactions and implications in disease states. Biochim Biophys Acta. 2009; 1791(7):646-58. PMC: 2757135. DOI: 10.1016/j.bbalip.2009.03.001. View

Errico A, Ballabio A, Rugarli E . Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002; 11(2):153-63. DOI: 10.1093/hmg/11.2.153. View

10.

Bieniossek C, Schalch T, Bumann M, Meister M, Meier R, Baumann U . The molecular architecture of the metalloprotease FtsH. Proc Natl Acad Sci U S A. 2006; 103(9):3066-71. PMC: 1413944. DOI: 10.1073/pnas.0600031103. View

11.

Erzberger J, Berger J . Evolutionary relationships and structural mechanisms of AAA+ proteins. Annu Rev Biophys Biomol Struct. 2006; 35:93-114. DOI: 10.1146/annurev.biophys.35.040405.101933. View

12.

Boldogh I, Pon L . Mitochondria on the move. Trends Cell Biol. 2007; 17(10):502-10. DOI: 10.1016/j.tcb.2007.07.008. View

13.

He J, Mao C, Reyes A, Sembongi H, Di Re M, Granycome C . The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization. J Cell Biol. 2007; 176(2):141-6. PMC: 2063933. DOI: 10.1083/jcb.200609158. View

14.

Babst M, Wendland B, Estepa E, Emr S . The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function. EMBO J. 1998; 17(11):2982-93. PMC: 1170638. DOI: 10.1093/emboj/17.11.2982. View

15.

Stan T, Brix J, Schneider-Mergener J, Pfanner N, Neupert W, Rapaport D . Mitochondrial protein import: recognition of internal import signals of BCS1 by the TOM complex. Mol Cell Biol. 2003; 23(7):2239-50. PMC: 150725. DOI: 10.1128/MCB.23.7.2239-2250.2003. View

16.

Rouiller I, Butel V, Latterich M, Milligan R . A major conformational change in p97 AAA ATPase upon ATP binding. Mol Cell. 2001; 6(6):1485-90. DOI: 10.1016/s1097-2765(00)00144-1. View

17.

Westermann B . Molecular machinery of mitochondrial fusion and fission. J Biol Chem. 2008; 283(20):13501-5. DOI: 10.1074/jbc.R800011200. View

18.

Griparic L, van der Wel N, Orozco I, Peters P, van der Bliek A . Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem. 2004; 279(18):18792-8. DOI: 10.1074/jbc.M400920200. View

19.

Hackenbrock C, Miller K . The distribution of anionic sites on the surfaces of mitochondrial membranes. Visual probing with polycationic ferritin. J Cell Biol. 1975; 65(3):615-30. PMC: 2109436. DOI: 10.1083/jcb.65.3.615. View

20.

Guertin D, Guntur K, Bell G, Thoreen C, Sabatini D . Functional genomics identifies TOR-regulated genes that control growth and division. Curr Biol. 2006; 16(10):958-70. DOI: 10.1016/j.cub.2006.03.084. View