Go to the content. | Move to the navigation | Go to the site search | Go to the menu | Contacts | Accessibility

| Create Account

Rigoni, Giovanni (2019) ATAD3 protein family: Molecular dissection of the ATAD3A dual role on the maintenance of mitochondrial ultrastructure and mtDNA-Nucleoid organization. [Ph.D. thesis]

Full text disponibile come:

[img]PDF Document (Giovanni_Rigoni_tesi)
Thesis not accessible until 02 December 2039 for intellectual property related reasons.
Visibile to: nobody


Abstract (italian or english)

Mitochondria are key organelles in a variety of cellular functions such as ATP production, calcium homeostasis, cell differentiation, and apoptosis. All these functions are possible thanks to the complicated
mitochondrial ultrastructure that results in the compartmentalization of the different biochemical processes. An example of this is the cristae compartment that host the oxidative phosphorylation machinery, existing a direct correlation between the cristae density and the respiratory capacity of mitochondria. Moreover, the mitochondrial ultrastructure is crucial for the mitochondrial function, indeed, thinner cristae favor the assembly of respiratory complexes in supercomplexes improving the respiratory efficiency. Therefore, the ultrastructure has become an indicator of the mitochondrial functional status and the study of specific
ultrastructural parameters is currently used to describe a dysfunction. In this thesis, by using a dynamic complexomic analysis to identify new cristae remodeling modulators, we have recognized the protein ATAD3A as a highly interesting candidate to participate in the process. Although previous studies pointed to ATAD3A as a regulator of mitochondrial ultrastructure based
on results obtained after silencing, no details about the molecular mechanism have been revealed. In addition, ATAD3A have been also implicated in many other cellular processes like cholesterol transport, apoptosis and nucleoid-mtDNA stability. The main goal of this work was to understand whether and how ATAD3A regulates mitochondrial structure and whether this is somehow correlated with its implication in mtDNA stability.
To address these questions, we used a variety of biochemical and proteomic approaches, that in combination with proper genetic models have led us to the data presented in this work. We have identified by dynamic complexomic analysis three different complexes of ATAD3A at 1MDa, 500kDa and 250kDa. The observation that only the 500kDa complex is disrupted during the cristae remodeling, and that OPA1 was comigrating in the same disrupted complex, led us to hypothesize its involvement in the cristae maintenance. Indeed, ATAD3A silencing or overexpression was able to decrease or increase the number of cristae, respectively. Moreover, this effect was accompanied by alterations on the nucleoid and mtDNA copy number. By using specific ATAD3A mutant in the coiled-coil (CCD) or ATPase domain of ATAD3A we demonstrated that the ATPase is required for the cristae maintenance while the CCD seems to be involved in nucleoid organization. Our experiments also excluded the participation of the ATAD3A oligomerization in the cristae maintenance.
The analysis of the ATAD3A complexes in presence of the different mutants further supported the involvement of the 500kDa complex in the process of cristae maintenance since the ATAD3A ATPase-mutant, that does not maintain cristae does not assemble on it. On the contrary, the CCD-mutant that induces cristae biogenesis assembles in the 500kDa complex. Our data also support the idea that ATAD3A 500kDa complex act as a scaffold protein that allows OPA1 to assemble together cooperating in the cristae biogenesis process.
We have also studied the role of the ATAD3A 1MDa complex, which looking in our complexomic analysis, appeared enriched in mitoribosomal and other proteins suggested to be involved in nucleoid and mtDNA stability, suggesting the involvement in the process. To support this idea, cells lacking the mtDNA do not present the ATAD3A 1MDa complex, and also control treated shortly with EtBr display a significant reduction of the same complex. Since the CCD-mutant is not assembling in the 1MDa complex, we analyzed
nucleoids in presence of the ATAD3A wild type or mutants after silencing of the endogenous protein. This results further confirm the involvement of the 1MDa in nucleoid organization since the CCD mutant exhibited a decrease in nucleoid are that was not present with the wild type or ATPase-mutant.
Overall our data demonstrate a dual role of ATAD3A in cristae biogenesis and nucleoid-mtDNA stability that depends on the different domains: the coiled-coil domain is required for nucleoid organization and the ATPase domain for cristae biogenesis.
Additional studies have been done in this PhD thesis to understand whether and how ATAD3B might be able or not to complement the absence of ATAD3A, or if as previously proposed it acts as a dominant
negative for ATAD3A. Our work supports the latter hypothesis, that seems to be mediated by the direct interaction of ATAD3A and ATAD3B in the 1MDa complex. Surprisingly, our data show that ATAD3B can revert the pathological mitochondrial phenotype observed in cells expressing the ATPase mutant, suggesting that the nullifying effect of ATAD3B is not specific for the wild type protein. Further experiments are required to confirm these results.

EPrint type:Ph.D. thesis
Tutor:Soriano, Maria Eugenia
Data di deposito della tesi:02 December 2019
Anno di Pubblicazione:02 November 2019
Key Words:ATAD3, mitochondrial ultrastructure, nucleoids, mitochondrial DNA, network morphology
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Biologia
Codice ID:12274
Depositato il:10 Feb 2021 19:06
Simple Metadata
Full Metadata
EndNote Format


I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Palade GE. The fine structure of mitochondria. Anat Rec. 1952;114:427–51. Cerca con Google

2. Mannella CA, Marko M, Penczek P, Barnard D, Frank J. The internal compartmentation of rat‐liver mitochondria: Tomographic study using the high‐voltage transmission electron microscope. Microsc Res Tech. 1994;27:278–83. Cerca con Google

3. Hackenbrock CR. Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci U S A. 1968;61:598–605. Cerca con Google

4. De Kroon AIPM, Dolis D, Mayer A, Lill R, De Kruijff B. Phospholipid composition of highly purified mitochondrial outer membranes of rat liver and Neurospora crassa. Is cardiolipin present in the mitochondrial outer membrane? Biochim Biophys Acta - Biomembr. 1997;1325:108–16. Cerca con Google

5. Horvath SE, Daum G. Lipids of mitochondria. Prog Lipid Res. 2013;52:590–614. doi:10.1016/j.plipres.2013.07.002. Cerca con Google

6. Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon‐Larose K, et al. OPA1‐dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 2014;33:2676–91. Cerca con Google

7. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, et al. A Distinct Pathway Remodels Mitochondrial Cristae and Mobilizes Cytochrome c during Apoptosis. Cell Press. 2002;2:55–67. Cerca con Google

8. Vincent AE, Ng YS, White K, Davey T, Mannella C, Falkous G, et al. The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy. Sci Rep. 2016;6 August:1–12. Cerca con Google

9. Frey TG, Renken CW, Perkins GA. Insight into mitochondrial structure and function from electron tomography. Biochim Biophys Acta - Bioenerg. 2002;1555:196–203. Cerca con Google

10. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013;155:160–71. doi:10.1016/j.cell.2013.08.032. Cerca con Google

11. Pernas L, Scorrano L. Mito-Morphosis: Mitochondrial Fusion, Fission, and Cristae Remodeling as Key Mediators of Cellular Function. Annu Rev Physiol. 2016;78:505–31. Cerca con Google

12. Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko G V., Rudka T, et al. OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion. Cell. 2006;126:177–89. Cerca con Google

13. Cipolat S, De Brito OM, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004;101:15927–32. Cerca con Google

14. Li D, Wang J, Jin Z, Zhang Z. Structural and evolutionary characteristics of dynamin-related GTPase OPA1. PeerJ. 2019;7 Imm:e7285. Cerca con Google

15. Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol. 2014;204:919–29. Cerca con Google

16. Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K, et al. Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling. Cell. 2006;126:163–75. Cerca con Google

17. Cesnekova J, Rodinova M, Hansikova H, Zeman J, Stiburek L. Loss of mitochondrial AAA proteases AFG3L2 and YME1L impairs mitochondrial structure and respiratory chain biogenesis. Int J Mol Sci. 2018;19. Cerca con Google

18. Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D, et al. Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol. 2009;187:1023–36. Cerca con Google

19. Tadato B, Heymann JAW, Song Z, Hinshaw JE, Chan DC. OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet. 2010;19:2113–22. Cerca con Google

20. Glytsou C, Calvo E, Cogliati S, Mehrotra A, Anastasia I, Rigoni G, et al. Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control. Cell Rep. 2016;17:3024–34. Cerca con Google

21. Varanita T, Soriano ME, Romanello V, Zaglia T, Quintana-Cabrera R, Semenzato M, et al. The Opa1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab. 2015;21:834–44. Cerca con Google

22. Civiletto G, Varanita T, Cerutti R, Gorletta T, Barbaro S, Marchet S, et al. Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models. Cell Metab. 2015;21:845–54. doi:10.1016/j.cmet.2015.04.016. Cerca con Google

23. Quintana-Cabrera R, Quirin C, Glytsou C, Corrado M, Urbani A, Pellattiero A, et al. The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function. Nat Commun. 2018;9. Cerca con Google

24. Aaltonen MJ, Friedman JR, Osman C, Salin B, di Rago JP, Nunnari J, et al. MIC OS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. J Cell Biol. 2016;213:525–34. Cerca con Google

25. Hessenberger M, Zerbes RM, Rampelt H, Kunz S, Xavier AH, Purfürst B, et al. Regulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions. Nat Commun. 2017;8 May. Cerca con Google

26. 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;32:1173–88. Cerca con Google

27. Li H, Ruan Y, Zhang K, Jian F, Hu C, Miao L, et al. Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization. Cell Death Differ. 2016;23:380–92. Cerca con Google

28. Rampelt H, Bohnert M, Zerbes RM, Horvath SE, Warscheid B, Pfanner N, et al. Mic10, a Core Subunit of the Mitochondrial Contact Site and Cristae Organizing System, Interacts with the Dimeric F1Fo-ATP Synthase. J Mol Biol. 2017;429:1162–70. doi:10.1016/j.jmb.2017.03.006. Cerca con Google

29. Guarani V, McNeill EM, Paulo JA, Huttlin EL, Fröhlich F, Gygi SP, et al. QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology. Elife. 2015;4 MAY:1–23. Cerca con Google

30. Koob S, Barrera M, Anand R, Reichert AS. The non-glycosylated isoform of MIC26 is a constituent of the mammalian MICOS complex and promotes formation of crista junctions. Biochim Biophys Acta - Mol Cell Res. 2015;1853:1551–63. doi:10.1016/j.bbamcr.2015.03.004. Cerca con Google

31. Weber TA, Koob S, Heide H, Wittig I, Head B, van der Bliek A, et al. APOOL Is a Cardiolipin-Binding Constituent of the Mitofilin/MINOS Protein Complex Determining Cristae Morphology in Mammalian Mitochondria. PLoS One. 2013;8. Cerca con Google

32. Allen RD. Membrane tubulation and proton pumps. Protoplasma. 1995. Cerca con Google

33. Arselin G, Vaillier J, Salin B, Schaeffer J, Giraud MF, Dautant A, et al. The modulation in subunits e and g amounts of yeast ATP synthase modifies mitochondrial cristae morphology. J Biol Chem. 2004;279:40392–9. Cerca con Google

34. Giraud MF, Paumard P, Soubannier V, Vaillier J, Arselin G, Salin B, et al. Is there a relationship between the supramolecular organization of the mitochondrial ATP synthase and the formation of cristae? Biochim Biophys Acta - Bioenerg. 2002;1555:174–80. Cerca con Google

35. Arnold I, Pfeiffer K, Neupert W, Stuart RA, Schägger H. Yeast mitochondrial F1F0-ATP synthase exists as a dimer: Identification of three dimer-specific subunits. EMBO J. 1998;17:7170–8. Cerca con Google

36. Habersetzer J, Larrieu I, Priault M, Salin B, Rossignol R, Brèthes D, et al. Human F 1 F 0 ATP Synthase, Mitochondrial Ultrastructure and OXPHOS Impairment: A (Super-)Complex Matter? PLoS One. 2013;8. Cerca con Google

37. Hahn A, Parey K, Bublitz M, Mills DJ, Zickermann V, Vonck J, et al. Structure of a Complete ATP Synthase Dimer Reveals the Molecular Basis of Inner Mitochondrial Membrane Morphology. Mol Cell. 2016;63:445–56. Cerca con Google

38. Mühleip AW, Joos F, Wigge C, Frangakis AS, Kühlbrandt W, Davies KM. Helical arrays of U-shaped ATP synthase dimers form tubular cristae in ciliate mitochondria. Proc Natl Acad Sci U S A. 2016;113:8442–7. Cerca con Google

39. Davies KM, Anselmi C, Wittig I, Faraldo-Gómez JD, Kühlbrandt W. Structure of the yeast F 1F o-ATP synthase dimer and its role in shaping the mitochondrial cristae. Proc Natl Acad Sci U S A. 2012;109:13602–7. Cerca con Google

40. Blum TB, Hahn A, Meier T, Davies KM, Kühlbrandt W. Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows. Proc Natl Acad Sci U S A. 2019;116:4250–5. Cerca con Google

41. Zimorski V, Ku C, Martin WF, Gould SB. Endosymbiotic theory for organelle origins. Curr Opin Microbiol. 2014;22:38–48. doi:10.1016/j.mib.2014.09.008. Cerca con Google

42. Sato M, Sato K. Maternal inheritance of mitochondrial DNA by diverse mechanisms to eliminate paternal mitochondrial DNA. Biochim Biophys Acta - Mol Cell Res. 2013;1833:1979–84. doi:10.1016/j.bbamcr.2013.03.010. Cerca con Google

43. Luo S, Valencia CA, Zhang J, Lee NC, Slone J, Gui B, et al. Biparental inheritance of mitochondrial DNA in humans. Proc Natl Acad Sci U S A. 2018;115:13039–44. Cerca con Google

44. Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. Reconstitution of a minimal mtDNA replisome in vitro. EMBO J. 2004;23:2423–9. Cerca con Google

45. Copeland WC. Defects in Mitochondrial DNA Replication and Human Disease. Crit Rev Biochem Mol Biol. 2013;47:64–74. Cerca con Google

46. Falkenberg M. Mitochondrial DNA replication in mammalian cells: Overview of the pathway. Essays Biochem. 2018;62:287–96. Cerca con Google

47. Yang MY, Bowmaker M, Reyes A, Vergani L, Angeli P, Gringeri E, et al. Biased incorporation of ribonucleotides on the mitochondrial L-strand accounts for apparent strand-asymmetric DNA replication. Cell. 2002;111:495–505. Cerca con Google

48. Agaronyan K, Morozov YI, Anikin M, Temiakov D. Replication-transcription switch in human mitochondria. Science (80- ). 2015;347:548–51. Cerca con Google

49. Minczuk M, He J, Duch AM, Ettema TJ, Chlebowski A, Dzionek K, et al. TEFM (c17orf42) is necessary for transcription of human mtDNA. Nucleic Acids Res. 2011;39:4284–99. Cerca con Google

50. Ylikallio E, Tyynismaa H, Tsutsui H, Ide T, Suomalainen A. High mitochondrial DNA copy number has detrimental effects in mice. Hum Mol Genet. 2010;19:2695–705. Cerca con Google

51. Garrido N, Griparic L, Jokitalo E, Wartiovaara J, Van der Bliek AM, Spelbrink JN. Composition and dynamics of human mitochondrial nucleoids. Mol Biol Cell. 2003. Cerca con Google

52. Rajala N, Gerhold JM, Martinsson P, Klymov A, Spelbrink JN. Replication factors transiently associate with mtDNA at the mitochondrial inner membrane to facilitate replication. Nucleic Acids Res. 2014;42:952–67. Cerca con Google

53. Kasashima K, Endo H. Interaction of human mitochondrial transcription factor A in mitochondria: Its involvement in the dynamics of mitochondrial DNA nucleoids. Genes to Cells. 2015;20:1017–27. Cerca con Google

54. Hensen F, Cansiz S, Gerhold JM, Spelbrink JN. To be or not to be a nucleoid protein: A comparison of mass-spectrometry based approaches in the identification of potential mtDNA-nucleoid associated proteins. Biochimie. 2014;100:219–26. doi:10.1016/j.biochi.2013.09.017. Cerca con Google

55. Wang Y, Bogenhagen DF. Human mitochondrial DNA nucleoids are linked to protein folding machinery and metabolic enzymes at the mitochondrial inner membrane. J Biol Chem. 2006;281:25791–802. Cerca con Google

56. Rajala N, Hensen F, Wessels HJCT, Ives D, Gloerich J, Spelbrink JN. Whole cell formaldehyde cross-linking simplifies purification of mitochondrial nucleoids and associated proteins involved in mitochondrial gene expression. PLoS One. 2015;10:1–20. Cerca con Google

57. He J, Mao CC, 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;176:141–6. Cerca con Google

58. Gilkerson R, Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, et al. The Mitochondrial Nucleoid : Integrating. Cold Spring Harb Perspect Biol. 2013;:1–10. Cerca con Google

59. Gerhold JM, Cansiz-Arda S, Lohmus M, Engberg O, Reyes A, Van Rennes H, et al. Human Mitochondrial DNA-Protein Complexes Attach to a Cholesterol-Rich Membrane Structure. Sci Rep. 2015;5:1–15. doi:10.1038/srep15292. Cerca con Google

60. Mao CC, Holt IJ. Clinical and molecular aspects of diseases of mitochondrial DNA instability. Chang Gung Med J. 2009;32:354–69. Cerca con Google

61. Lee SR, Han J. Mitochondrial Nucleoid: Shield and Switch of the Mitochondrial Genome. Oxid Med Cell Longev. 2017;2017. Cerca con Google

62. Sousa JS, D’Imprima E, Vonck J. Mitochondrial respiratory chain complexes. 2018. Cerca con Google

63. Zeviani M, Di Donato S. Mitochondrial disorders. Brain. 2004;127:2153–72. doi:10.1093/brain/awh259. Cerca con Google

64. Lippe G, Coluccino G, Zancani M, Baratta W, Crusiz P. Mitochondrial F-ATP Synthase and Its Transition into an Energy-Dissipating Molecular Machine. Oxid Med Cell Longev. 2019;2019:8743257. Cerca con Google

65. Neupane P, Bhuju S, Thapa N, Bhattarai HK. ATP Synthase: Structure, Function and Inhibition. Biomol Concepts. 2019. Cerca con Google

66. Papa S, Martino PL, Capitanio G, Gaballo A, De Rasmo D, Signorile A, et al. The oxidative phosphorylation system in mammalian mitochondria. Adv Exp Med Biol. 2012. Cerca con Google

67. Holley AK, Bakthavatchalu V, Velez-Roman JM, St. Clair DK. Manganese superoxide dismutase: Guardian of the powerhouse. Int J Mol Sci. 2011;12:7114–62. Cerca con Google

68. D. Keilin EFH. Activity of the cytochrome system in heart muscle preparations. Biochem J. 1947;41:500–2. Cerca con Google

69. Hackenbrock CR, Chazotte B, Gupte SS. The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport. J Bioenerg Biomembr. 1986;18:331–368. Cerca con Google

70. Acin-Perez R, Enriquez JA. The function of the respiratory supercomplexes: The plasticity model. Biochim Biophys Acta - Bioenerg. 2014;1837:444–50. doi:10.1016/j.bbabio.2013.12.009. Cerca con Google

71. Cogliati S, Lorenzi I, Rigoni G, Caicci F, Soriano ME. Regulation of Mitochondrial Electron Transport Chain Assembly. J Mol Biol. 2018;430. Cerca con Google

72. Lapuente-Brun E, Moreno-Loshuertos R, Aciń-Pérez R, Latorre-Pellicer A, Colaś C, Balsa E, et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science (80- ). 2013;340:1567–70. Cerca con Google

73. Vukotic M, Oeljeklaus S, Wiese S, Vögtle FN, Meisinger C, Meyer HE, et al. Rcf1 mediates cytochrome oxidase assembly and respirasome formation, revealing heterogeneity of the enzyme complex. Cell Metab. 2012;15:336–47. Cerca con Google

74. An HJ, Cho G, Lee JO, Paik SG, Kim YS, Lee H. Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria. Proc Natl Acad Sci U S A. 2013;110:13014–9. Cerca con Google

75. Li T, Xian WJ, Gao Y, Jiang S, Yu QH, Zheng QC, et al. Higd1a Protects Cells from Lipotoxicity under High-Fat Exposure. Oxid Med Cell Longev. 2019;2019:6051262. Cerca con Google

76. Zhong X, Cui P, Cai Y, Wang L, He X, Long P, et al. Mitochondrial Dynamics Is Critical for the Full Pluripotency and Embryonic Developmental Potential of Pluripotent Stem Cells. Cell Metab. 2019;29:979-992.e4. doi:10.1016/j.cmet.2018.11.007. Cerca con Google

77. Folmes CDL, Nelson TJ, Martinez-fernandez A, Arrell DK, Lindor JZ, Dzeja PP, et al. Chines_Biologic characteristics. 2012;14:264–71. Cerca con Google

78. Prieto J, Seo AY, León M, Santacatterina F, Torresano L, Palomino-Schätzlein M, et al. MYC Induces a Hybrid Energetics Program Early in Cell Reprogramming. Stem Cell Reports. 2018;11:1479–92. Cerca con Google

79. Gomes LC, Benedetto G Di, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011;13:589–98. Cerca con Google

80. Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC. Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell. 2009. Cerca con Google

81. Enríquez JA, Cabezas-Herrera J, Bayona-Bafaluy MP, Attardi G. Very rare complementation between mitochondria carrying different mitochondrial DNA mutations points to intrinsic genetic autonomy of the organelles in cultured human cells. J Biol Chem. 2000. Cerca con Google

82. Lee H, Smith SB, Yoon Y. The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure. J Biol Chem. 2017;292:7115–30. Cerca con Google

83. Ban T, Kohno H, Ishihara T, Ishihara N. Relationship between OPA1 and cardiolipin in mitochondrial inner-membrane fusion. Biochim Biophys Acta - Bioenerg. 2018;1859:951–7. doi:10.1016/j.bbabio.2018.05.016. Cerca con Google

84. Sloat SR, Whitley BN, Engelhart EA, Hoppins S. Identification of a mitofusin specificity region that confers unique activities to Mfn1 and Mfn2. Mol Biol Cell. 2019;30:2309–19. Cerca con Google

85. Detmer SA, Chan DC. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol. 2007;176:405–14. Cerca con Google

86. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160:189–200. Cerca con Google

87. Muñoz JP, Ivanova S, Sánchez-Wandelmer J, Martínez-Cristóbal P, Noguera E, Sancho A, et al. Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J. 2013;32:2348–61. Cerca con Google

88. Cereghetti GM, Costa V, Scorrano L. Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin. Cell Death Differ. 2010;17:1785–94. Cerca con Google

89. Oettinghaus B, D’Alonzo D, Barbieri E, Restelli LM, Savoia C, Licci M, et al. DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress. Biochim Biophys Acta - Bioenerg. 2016;1857:1267–76. doi:10.1016/j.bbabio.2016.03.016. Cerca con Google

90. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. ER tubules mark sites of mitochondrial division. Science (80- ). 2011;334:358–62. Cerca con Google

91. Lewis SC, Uchiyama LF, Nunnari J. ER-mitochondria contacts couple mtDNA synthesis with Mitochondrial division in human cells. Science (80- ). 2016;353. Cerca con Google

92. Cho B, Cho HM, Jo Y, Kim HD, Song M, Moon C, et al. Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division. Nat Commun. 2017;8:1–17. doi:10.1038/ncomms15754. Cerca con Google

93. Smirnova E, Griparic L, Shurland D, Bliek AM Van Der. <Mol Biol Cell 2001 Smirnova.pdf>. 2001;12 August:2245–56. Cerca con Google

94. Francy CA, Clinton RW, Fröhlich C, Murphy C, Mears JA. Cryo-EM Studies of Drp1 Reveal Cardiolipin Interactions that Activate the Helical Oligomer. Sci Rep. 2017;7:1–12. Cerca con Google

95. Kalia R, Wang RYR, Yusuf A, Thomas P V., Agard DA, Shaw JM, et al. Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature. 2018;558:401–5. doi:10.1038/s41586-018-0211-2. Cerca con Google

96. Jofuku A, Ishihara N, Mihara K. Analysis of functional domains of rat mitochondrial Fis1, the mitochondrial fission-stimulating protein. Biochem Biophys Res Commun. 2005;333:650–9. Cerca con Google

97. Yoon Y, Krueger EW, Oswald BJ, McNiven MA. The Mitochondrial Protein hFis1 Regulates Mitochondrial Fission in Mammalian Cells through an Interaction with the Dynamin-Like Protein DLP1. Mol Cell Biol. 2003;23:5409–20. Cerca con Google

98. Losó n OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013;24:659–67. Cerca con Google

99. Yu R, Jin S, Lendahl U, Nistér M, Zhao J. Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery. EMBO J. 2019;38:1–21. Cerca con Google

100. Zhao J, Liu T, Jin S, Wang X, Qu M, Uhlén P, et al. Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. EMBO J. 2011;30:2762–78. Cerca con Google

101. Yu R, Liu T, Jin SB, Ning C, Lendahl U, Nistér M, et al. MIEF1/2 function as adaptors to recruit Drp1 to mitochondria and regulate the association of Drp1 with Mff. Sci Rep. 2017;7:1–16. Cerca con Google

102. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet. 2000;26:207–10. Cerca con Google

103. Gaier ED, Boudreault K, Nakata I, Janessian M, Skidd P, DelBono E, et al. Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status. Mol Vis. 2017;23 April:548–60. Cerca con Google

104. Zanna C, Ghelli A, Porcelli AM, Karbowski M, Youle RJ, Schimpf S, et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain. 2008;131:352–67. Cerca con Google

105. Kane MS, Alban J, Desquiret-Dumas V, Gueguen N, Ishak L, Ferre M, et al. Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. J Cell Mol Med. 2017;21:2284–97. Cerca con Google

106. Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissière A, et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy “plus” phenotypes. Brain. 2008;131:338–51. Cerca con Google

107. Liao C, Ashley N, Diot A, Morten K, Phadwal K, Williams A, et al. Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations. Neurology. 2017;88:131–42. Cerca con Google

108. Yu-Wai-Man P, Sitarz KS, Samuels DC, Griffiths PG, Reeve AK, Bindoff LA, et al. OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules. Hum Mol Genet. 2010;19:3043–52. Cerca con Google

109. Diaz F, Bayona-Bafaluy MP, Rana M, Mora M, Hao H, Moraes CT. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res. 2002;30:4626–33. Cerca con Google

110. Kowald A, Kirkwood TBL. Resolving the enigma of the clonal expansion of mtDNA deletions. Genes (Basel). 2018;9. Cerca con Google

111. Trifunov S, Pyle A, Valentino ML, Liguori R, Yu-Wai-Man P, Burté F, et al. Clonal expansion of mtDNA deletions: different disease models assessed by digital droplet PCR in single muscle cells. Sci Rep. 2018;8:1–10. Cerca con Google

112. Verhoeven K, Claeys KG, Züchner S, Schröder JM, Weis J, Ceuterick C, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129:2093–102. Cerca con Google

113. Ando M, Hashiguchi A, Okamoto Y, Yoshimura A, Hiramatsu Y, Yuan J, et al. Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. J Peripher Nerv Syst. 2017;22:191–9. Cerca con Google

114. Eschenbacher WH, Song M, Chen Y, Bhandari P, Zhao P, Jowdy CC, et al. Two Rare Human Mitofusin 2 Mutations Alter Mitochondrial Dynamics and Induce Retinal and Cardiac Pathology in Drosophila. PLoS One. 2012;7. Cerca con Google

115. Amiott EA, Lott P, Soto J, Kang PB, McCaffery JM, DiMauro S, et al. Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations. Exp Neurol. 2008. Cerca con Google

116. Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci. 2010;30:4232–40. Cerca con Google

117. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, Masuda K, et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol. 2009;11:958–66. doi:10.1038/ncb1907. Cerca con Google

118. Waterham HR, Koster J, Van Roermund CWT, Mooyer PAW, Wanders RJA, Leonard J V. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007;356:1736–41. Cerca con Google

119. Fahrner JA, Liu R, Perry MS, Klein J, Chan DC. A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy. Am J Med Genet Part A. 2016;170:2002–11. Cerca con Google

120. Gerber S, Charif M, Chevrollier A, Chaumette T, Angebault C, Kane MS, et al. Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission. Brain. 2017;140:2586–96. Cerca con Google

121. Shamseldin HE, Alshammari M, Al-Sheddi T, Salih MA, Alkhalidi H, Kentab A, et al. Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. J Med Genet. 2012;49:234–41. Cerca con Google

122. Koch J, Feichtinger RG, Freisinger P, Pies M, Schrödl F, Iuso A, et al. Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy. J Med Genet. 2016;53:270–8. Cerca con Google

123. Bartsakoulia M, Pyle A, Troncoso-Chandía D, Vial-Brizzi J, Paz-Fiblas M V., Duff J, et al. A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies. Hum Mol Genet. 2018;27:1186–95. Cerca con Google

124. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Yasutoshi, McFarland R, et al. Mitochondrial diseases. Nat Rev Dis Prim. 2016;2:1–22. Cerca con Google

125. Craven L, Alston CL, Taylor RW, Turnbull DM. Recent Advances in Mitochondrial Disease. Annu Rev Genomics Hum Genet. 2017;18:257–75. Cerca con Google

126. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017;241:236–50. Cerca con Google

127. Ahmed N, Ronchi D, Comi G Pietro. Genes and pathways involved in adult onset disorders featuring muscle mitochondrial DNA instability. Int J Mol Sci. 2015;16:18054–76. Cerca con Google

128. El-Hattab AW, Scaglia F. Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options. Neurotherapeutics. 2013;10:186–98. Cerca con Google

129. Tuppen HAL, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta - Bioenerg. 2010;1797:113–28. doi:10.1016/j.bbabio.2009.09.005. Cerca con Google

130. Milenkovic D, Matic S, kühl I, Ruzzenente B, Freyer C, Jemt E, et al. Twinkle is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication. Hum Mol Genet. 2013;22:1983–93. Cerca con Google

131. DeBalsi KL, Hoff KE, Copeland WC. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev. 2017;33:89–104. Cerca con Google

132. Miralles Fusté J, Shi Y, Wanrooij S, Zhu X, Jemt E, Persson Ö, et al. In Vivo Occupancy of Mitochondrial Single-Stranded DNA Binding Protein Supports the Strand Displacement Mode of DNA Replication. PLoS Genet. 2014;10. Cerca con Google

133. Kühl I, Miranda M, Posse V, Milenkovic D, Mourier A, Siira SJ, et al. POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA. Sci Adv. 2016;2:1–14. Cerca con Google

134. Wang L, Hellman U, Eriksson S. Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA. FEBS Lett. 1996;390:39–43. Cerca con Google

135. Sun R, Wang L. Thymidine kinase 2 enzyme kinetics elucidate the mechanism of thymidine-induced mitochondrial DNA depletion. Biochemistry. 2014;53:6142–50. Cerca con Google

136. Sun R, Eriksson S, Wang L. Mitochondrial thymidine kinase 2 but not deoxyguanosine kinase is up-regulated during the stationary growth phase of cultured cells. Nucleosides, Nucleotides and Nucleic Acids. 2014;33:282–6. Cerca con Google

137. Chen L, Liu T, Tran A, Lu X, Tomilov AA, Davies V, et al. OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. J Am Heart Assoc. 2012;1:1–12. Cerca con Google

138. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, et al. Mitochondrial fusion is required for mtdna stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010;141:280–9. Cerca con Google

139. Vielhaber S, Debska-Vielhaber G, Peeva V, Schoeler S, Kudin AP, Minin I, et al. Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion. Acta Neuropathol. 2013;125:245–56. doi:10.1007/s00401-012-1036-y. Cerca con Google

140. Harel T, Yoon WH, Garone C, Gu S, Coban-Akdemir Z, Eldomery MK, et al. Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. Am J Hum Genet. 2016;99:831–45. doi:10.1016/j.ajhg.2016.08.007. Cerca con Google

141. Cooper HM, Yang Y, Ylikallio E, Khairullin R, Woldegebriel R, Lin KL, et al. ATpase-deficient mitochondrial inner membrane protein ATAD3a disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. Hum Mol Genet. 2017;26:1432–43. Cerca con Google

142. Desai R, Frazier AE, Durigon R, Patel H, Jones AW, Rosa ID, et al. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain. 2017;140:1595–610. Cerca con Google

143. Goller T, Seibold UK, Kremmer E, Voos W, Kolanus W. Atad3 Function Is Essential for Early Post-Implantation Development in the Mouse. PLoS One. 2013;8. Cerca con Google

144. 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;30:1984–96. Cerca con Google

145. Peralta S, Goffart S, Williams SL, Diaz F, Garcia S, Nissanka N, et al. ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels. J Cell Sci. 2018;131. Cerca con Google

146. He J, Cooper HM, Reyes A, Di Re M, Sembongi H, Gao J, et al. Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis. Nucleic Acids Res. 2012;40:6109–21. Cerca con Google

147. Bogenhagen DF, Rousseau D, Burke S. The layered structure of human mitochondrial DNA nucleoids. J Biol Chem. 2008;283:3665–75. Cerca con Google

148. Holt IJ, He J, Mao CC, Boyd-Kirkup JD, Martinsson P, Sembongi H, et al. Mammalian mitochondrial nucleoids: Organizing an independently minded genome. Mitochondrion. 2007;7:311–21. Cerca con Google

149. Zhang T, Du W, Wilson AF, Namekawa SH, Andreassen PR, Meetei AR, et al. Fancd2 in vivo interaction network reveals a non-canonical role in mitochondrial function. Sci Rep. 2017;7:1–11. doi:10.1038/srep45626. Cerca con Google

150. Merle N, Féraud O, Gilquin B, Hubstenberger A, Kieffer-Jacquinot S, Assard N, et al. ATAD3B is a human embryonic stem cell specific mitochondrial protein, re-expressed in cancer cells, that functions as dominant negative for the ubiquitous ATAD3A. Mitochondrion. 2012;12:441–8. doi:10.1016/j.mito.2012.05.005. Cerca con Google

151. 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;314:2870–83. Cerca con Google

152. Liu X, Li G, Ai L, Ye Q, Yu T, Yang B. Prognostic value of ATAD3 gene cluster expression in hepatocellular carcinoma. Oncol Lett. 2019;:1304–10. Cerca con Google

153. Vowinckel J, Hartl J, Butler R, Ralser M. MitoLoc: A method for the simultaneous quantification of mitochondrial network morphology and membrane potential in single cells. Mitochondrion. 2015;24:77–86. doi:10.1016/j.mito.2015.07.001. Cerca con Google

154. Frezza C, Cipolat S, Scorrano L. Organelle isolation: Functional mitochondria from mouse liver, muscle and cultured filroblasts. Nat Protoc. 2007;2:287–95. Cerca con Google

155. Guaras A, Calvo EP-CE, Perez RA, Loureiro-Lopez M, Pujol C, Martınez-Carrascoso I, et al. The CoQH2/CoQ Ratio Serves as a Sensor of Respiratory Chain Efficienc. Cell Rep. 2016;15:197–209. Cerca con Google

156. Franzolin E, Salata C, Bianchi V, Rampazzo C. The deoxynucleoside triphosphate triphosphohydrolase activity of SAMHD1 protein contributes to the mitochondrial DNA depletion associated with genetic deficiency of deoxyguanosine kinase. J Biol Chem. 2015;290:25986–96. Cerca con Google

157. Bahat A, Goldman A, Zaltsman Y, Khan DH, Halperin C, Amzallag E, et al. MTCH2-mediated mitochondrial fusion drives exit from naïve pluripotency in embryonic stem cells. Nat Commun. 2018;9:1–11. doi:10.1038/s41467-018-07519-w. Cerca con Google

158. Dimauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med. 2005;37:222–32. Cerca con Google

159. MacVicar T, Langer T. OPA1 processing in cell death and disease - the long and short of it. J Cell Sci. 2016;129:2297–306. Cerca con Google

160. Quintana-Cabrera R, Mehrotra A, Rigoni G, Soriano ME. Who and how in the regulation of mitochondrial cristae shape and function. Biochem Biophys Res Commun. 2018;500. Cerca con Google

Solo per lo Staff dell Archivio: Modifica questo record