Armadillo repeat-containing protein 1 is a dual localization protein associated with mitochondrial intermembrane space bridging complex

Autoři: Fabienne Wagner aff001;  Tobias C. Kunz aff001;  Suvagata R. Chowdhury aff001;  Bernd Thiede aff003;  Martin Fraunholz aff001;  Debora Eger aff001;  Vera Kozjak-Pavlovic aff001
Působiště autorů: Department of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany aff001;  German Cancer Research Center (DKFZ), Heidelberg, Germany aff002;  Department of Biosciences, University of Oslo, Oslo, Norway aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Cristae architecture is important for the function of mitochondria, the organelles that play the central role in many cellular processes. The mitochondrial contact site and cristae organizing system (MICOS) together with the sorting and assembly machinery (SAM) forms the mitochondrial intermembrane space bridging complex (MIB), a large protein complex present in mammalian mitochondria that partakes in the formation and maintenance of cristae. We report here a new subunit of the mammalian MICOS/MIB complex, an armadillo repeat-containing protein 1 (ArmC1). ArmC1 localizes both to cytosol and mitochondria, where it associates with the outer mitochondrial membrane through its carboxy-terminus. ArmC1 interacts with other constituents of the MICOS/MIB complex and its amounts are reduced upon MICOS/MIB complex depletion. Mitochondria lacking ArmC1 do not show defects in cristae structure, respiration or protein content, but appear fragmented and with reduced motility. ArmC1 represents therefore a peripheral MICOS/MIB component that appears to play a role in mitochondrial distribution in the cell.

Klíčová slova:

Cell staining – Confocal microscopy – Cytosol – HeLa cells – Immunoprecipitation – Mitochondria – Outer membrane proteins – Small interfering RNAs


1. Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11:872. doi: 10.1038/nrm3013 21102612

2. Endo T, Yamano K. Transport of proteins across or into the mitochondrial outer membrane. Biochim Biophys Acta Mol Cell Res. 2010;1803(6):706–14. doi: 10.1016/j.bbamcr.2009.11.007 19945489

3. Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol. 2019. doi: 10.1038/s41580-018-0092-0 30626975

4. Vogel F, Bornhövd C, Neupert W, Reichert AS. Dynamic subcompartmentalization of the mitochondrial inner membrane. J Cell Biol. 2006;175(2):237–47. doi: 10.1083/jcb.200605138 17043137

5. Harner M, Korner C, Walther D, Mokranjac D, Kaesmacher J, Welsch U, et al. The mitochondrial contact site complex, a determinant of mitochondrial architecture. EMBO J. 2011;30(21):4356–70. doi: 10.1038/emboj.2011.379 22009199

6. Hoppins S, Collins SR, Cassidy-Stone A, Hummel E, DeVay RM, Lackner LL, et al. A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. J Cell Biol. 2011;195(2):323–40. doi: 10.1083/jcb.201107053 21987634

7. von der Malsburg K, Müller Judith M, Bohnert M, Oeljeklaus S, Kwiatkowska P, Becker T, et al. Dual Role of Mitofilin in Mitochondrial Membrane Organization and Protein Biogenesis. Dev Cell. 2011;21(4):694–707. doi: 10.1016/j.devcel.2011.08.026 21944719

8. Pfanner N, van der Laan M, Amati P, Capaldi RA, Caudy AA, Chacinska A, et al. Uniform nomenclature for the mitochondrial contact site and cristae organizing system. J Cell Bio. 2014;204(7):1083–6. doi: 10.1083/jcb.201401006 24687277

9. Xie J, Marusich MF, Souda P, Whitelegge J, Capaldi RA. The mitochondrial inner membrane protein Mitofilin exists as a complex with SAM50, metaxins 1 and 2, coiled-coil-helix coiled-coil-helix domain-containing protein 3 and 6 and DnaJC11. FEBS Lett. 2007;581(18):3545–9. doi: 10.1016/j.febslet.2007.06.052 17624330

10. Ott C, Dorsch E, Fraunholz M, Straub S, Kozjak-Pavlovic V. Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits. PLoS One. 2015;10(3):e0120213. doi: 10.1371/journal.pone.0120213 25781180

11. Kozjak-Pavlovic V. The MICOS complex of human mitochondria. Cell Tissue Res. 2017;367(1):83–93. doi: 10.1007/s00441-016-2433-7 27245231

12. Odgren PR, Toukatly G, Bangs PL, Gilmore R, Fey EG. Molecular characterization of mitofilin (HMP), a mitochondria-associated protein with predicted coiled coil and intermembrane space targeting domains. J Cell Sci. 1996;109(9):2253.

13. Gieffers C, Korioth F, Heimann P, Ungermann C, Frey J. Mitofilin Is a Transmembrane Protein of the Inner Mitochondrial Membrane Expressed as Two Isoforms. Exp Cell Res. 1997;232(2):395–9. doi: 10.1006/excr.1997.3539 9168817

14. Kozjak-Pavlovic V, Prell F, Thiede B, Gotz M, Wosiek D, Ott C, et al. C1orf163/RESA1 is a novel mitochondrial intermembrane space protein connected to respiratory chain assembly. J Mol Biol. 2014;426(4):908–20. doi: 10.1016/j.jmb.2013.12.001 24333015

15. Ioakeimidis F, Ott C, Kozjak-Pavlovic V, Violitzi F, Rinotas V, Makrinou E, et al. A Splicing Mutation in the Novel Mitochondrial Protein DNAJC11 Causes Motor Neuron Pathology Associated with Cristae Disorganization, and Lymphoid Abnormalities in Mice. PLoS ONE. 2014;9(8):e104237. doi: 10.1371/journal.pone.0104237 25111180

16. Huynen MA, Mühlmeister M, Gotthardt K, Guerrero-Castillo S, Brandt U. Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. Biochim Biophys Acta Mol Cell Res. 2016;1863(1):91–101. doi: 10.1016/j.bbamcr.2015.10.009 26477565

17. Guarani V, McNeill EM, Paulo JA, Huttlin EL, Frohlich F, Gygi SP, et al. QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology. Elife. 2015;4. doi: 10.7554/eLife.06265 25997101

18. Peifer M, Berg S, Reynolds AB. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell. 1994;76(5):789–91. doi: 10.1016/0092-8674(94)90353-0 7907279

19. Ott C, Ross K, Straub S, Thiede B, Gotz M, Goosmann C, et al. Sam50 functions in mitochondrial intermembrane space bridging and biogenesis of respiratory complexes. Mol Cell Biol. 2012;32(6):1173–88. Epub 2012/01/19. doi: 10.1128/MCB.06388-11 22252321

20. Coates JC. Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol. 2003;13(9):463–71. doi: 10.1016/S0962-8924(03)00167-3 12946625

21. Xu W, Kimelman D. Mechanistic insights from structural studies of beta-catenin and its binding partners. J Cell Sci. 2007;120(Pt 19):3337–44. doi: 10.1242/jcs.013771 17881495

22. Park Y-U, Jeong J, Lee H, Mun JY, Kim J-H, Lee JS, et al. Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proc Natl Acad Sci USA. 2010;107(41):17785–90. doi: 10.1073/pnas.1004361107 20880836

23. Medina-Dols A, Ortega-Vila B, Piñero-Martos E, Cisneros-Barroso E, Pol-Fuster J, Ruiz-Guerra L, et al. Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation. Hum Mol Gen. 2016;25(19):4157–69. doi: 10.1093/hmg/ddw250 27466199

24. James R, Adams RR, Christie S, Buchanan SR, Porteous DJ, Millar JK. Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Mol Cell Neurosci. 2004;26(1):112–22. doi: 10.1016/j.mcn.2004.01.013 15121183

25. Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol. 1997;139(5):1281–92. doi: 10.1083/jcb.139.5.1281 9382873

26. Schellenberg B, Wang P, Keeble JA, Rodriguez-Enriquez R, Walker S, Owens TW, et al. Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell. 2013;49(5):959–71. doi: 10.1016/j.molcel.2012.12.022 23375500

27. Gilquin B, Taillebourg E, Cherradi N, Hubstenberger A, Gay O, Merle N, et al. The AAA+ ATPase ATAD3A Controls Mitochondrial Dynamics at the Interface of the Inner and Outer Membranes. Mol Cell Biol. 2010;30(8):1984–96. doi: 10.1128/MCB.00007-10 20154147

28. He J, Mao C-C, Reyes A, Sembongi H, Di Re M, Granycome C, et al. The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization. J Cell Biol. 2007;176(2):141–6. doi: 10.1083/jcb.200609158 17210950

29. Rolland T, Taşan M, Charloteaux B, Pevzner Samuel J, Zhong Q, Sahni N, et al. A Proteome-Scale Map of the Human Interactome Network. Cell. 2014;159(5):1212–26. doi: 10.1016/j.cell.2014.10.050 25416956

30. Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Brief Bioinform. 2011;12(5):449–62. Epub 08/27. doi: 10.1093/bib/bbr042 21873635

31. López-Doménech G, Serrat R, Mirra S, D'Aniello S, Somorjai I, Abad A, et al. The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2. Nature Comm. 2012;3:814. doi: 10.1038/ncomms1829 22569362

32. Chen Z, Lei C, Wang C, Li N, Srivastava M, Tang M, et al. Global phosphoproteomic analysis reveals ARMC10 as an AMPK substrate that regulates mitochondrial dynamics. Nat Commun. 2019;10(1):104–. doi: 10.1038/s41467-018-08004-0 30631047

33. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJR, et al. Toward a Comprehensive Characterization of a Human Cancer Cell Phosphoproteome. J Prot Res. 2013;12(1):260–71. doi: 10.1021/pr300630k 23186163

34. Wiznerowicz M, Trono D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol. 2003;77(16):8957–61. doi: 10.1128/JVI.77.16.8957-8961.2003 12885912

35. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat protoc. 2013;8(11):2281–308. doi: 10.1038/nprot.2013.143 24157548

36. Chowdhury SR, Reimer A, Sharan M, Kozjak-Pavlovic V, Eulalio A, Prusty BK, et al. Chlamydia preserves the mitochondrial network necessary for replication via microRNA-dependent inhibition of fission. J Cell Biol. 2017;216(4):1071–89. doi: 10.1083/jcb.201608063 28330939

37. Humphries AD, Streimann IC, Stojanovski D, Johnston AJ, Yano M, Hoogenraad NJ, et al. Dissection of the mitochondrial import and assembly pathway for human Tom40. J Biol Chem. 2005;280(12):11535–43. doi: 10.1074/jbc.M413816200 15644312

38. Kozjak V, Wiedemann N, Milenkovic D, Lohaus C, Meyer HE, Guiard B, et al. An essential role of Sam50 in the protein sorting and assembly machinery of the mitochondrial outer membrane. J Biol Chem. 2003;278(49):48520–3. doi: 10.1074/jbc.C300442200 14570913

39. Kozjak-Pavlovic V, Ott C, Gotz M, Rudel T. Neisserial Omp85 protein is selectively recognized and assembled into functional complexes in the outer membrane of human mitochondria. J Biol Chem. 2011;286(30):27019–26. Epub 2011/06/10. doi: 10.1074/jbc.M111.232249 21652692

40. Wu M, Neilson A, Swift AL, Moran R, Tamagnine J, Parslow D, et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am J Physiol Cell Physiol. 2007;292(1):C125–36. doi: 10.1152/ajpcell.00247.2006 16971499

41. Schägger H, von Jagow G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal Biochem. 1991;199(2):223–31. doi: 10.1016/0003-2697(91)90094-a 1812789

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