nach oben

Erschienen in:

01.08.2011 | Original Paper

Nuclear localization of the mitochondrial ncRNAs in normal and cancer cells

verfasst von: Eduardo Landerer, Jaime Villegas, Veronica A. Burzio, Luciana Oliveira, Claudio Villota, Constanza Lopez, Franko Restovic, Ronny Martinez, Octavio Castillo, Luis O. Burzio

Erschienen in: Cellular Oncology | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

Background

We have previously shown a differential expression of a family of mitochondrial ncRNAs in normal and cancer cells. Normal proliferating cells and cancer cells express the sense mitochondrial ncRNA (SncmtRNA). In addition, while normal proliferating cells express two antisense mitochondrial ncRNAs (ASncmtRNAs-1 and −2), these transcripts seem to be universally down-regulated in cancer cells. In situ hybridization (ISH) of some normal and cancer tissues reveals nuclear localization of these transcripts suggesting that they are exported from mitochondria.

Methods

FISH and confocal microscopy, in situ digestion with RNase previous to ISH and electron microscopy ISH was employed to confirm the extra-mitochondrial localization of the SncmtRNA and the ASncmtRNAs in normal proliferating and cancer cells of human and mouse.

Results

In normal human kidney and mouse testis the SncmtRNA and the ASncmtRNAs were found outside the organelle and especially localized in the nucleus associated to heterochromatin. In cancer cells, only the SncmtRNA was expressed and was found associated to heterochromatin and nucleoli.

Conclusion

The ubiquitous localization of these mitochondrial transcripts in the nucleus suggests that they are new players in the mitochondrial-nuclear communication pathway or retrograde signaling. Down regulation of the ASncmtRNAs seems to be an important step on neoplastic transformation and cancer progression.

O. Warburg, On respiratory impairment in cancer cells. Science 124, 269–270 (1956)PubMed

J.S. Carew, P. Huang, Mitochondrial defects in cancer. Mol Cancer 1, 1–9 (2002)CrossRef

D.C. Wallace, W.W. Fan, The pathophysiology of mitochondrial disease as modeled in the mouse. Genes Dev 23, 1714–1736 (2009)PubMedCrossRef

G. Biswas, O.A. Adebanjo, B.D. Freedman, H.K. Anandatheerthavarada, C. Vijayasarathy, M. Zaidi, M. Kotlikoff, N.G. Avadhani, Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. EMBO J 18, 522–533 (1999)PubMedCrossRef

G. Biswas, H.K. Anandatheerthavarada, N.G. Avadhani, Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes. Cell Death Differ 12, 266–278 (2005)PubMedCrossRef

G. Amuthan, G. Biswas, S.Y. Zhang, A. Klein-Szanto, C. Vijayasarathy, N.G. Avadhani, Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J 20, 1910–1920 (2001)PubMedCrossRef

G. Amuthan, G. Biswas, H.K. Ananadatheerthavarada, C. Vijayasarathy, H.M. Shephard, N.G. Avadhani, Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 21, 7839–7849 (2002)PubMedCrossRef

R.A. Butow, N.G. Avadhani, Mitochondrial signaling: the retrograde response. Mol. Cell 14, 1–15 (2004)PubMedCrossRef

Z. Liu, R.A. Butow, Mitochondrial retrograde signaling. Annu Rev Genet 40, 159–185 (2006)PubMedCrossRef

10.

M.T. Ryan, N.J. Hoogenraad, Mitochondrial-nuclear communications. Ann Rev Biochem 76, 701–722 (2007)PubMedCrossRef

11.

G. Biswas, H.K. Anandatheerthavarada, M. Zaidi, N.G. Avadhani, Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta. J Cell Biol 161, 507–519 (2003)PubMedCrossRef

12.

M. Guha, S. Srinivasan, G. Biswas, N.G. Avadhani, Activation of a novel calcineurin-mediated insulin-like growth factor-1 receptor pathway, altered metabolism, and tumor cell invasion in cells subjected to mitochondrial respiratory stress. J Biol Chem 282, 14536–14546 (2007)PubMedCrossRef

13.

S.M. Schieke, T. Finkel, Mitochondrial signaling, TOR and life span. Biol Chem 387, 1357–1361 (2006)PubMedCrossRef

14.

G. Biswas, S. Srinivasan, H.K. Anandatheerthavarada, N.G. Avadhani, Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling. Proc Natl Acad Sci U S A 105, 186–191 (2008)PubMedCrossRef

15.

J. Villegas, V.A. Burzio, C. Villota, E. Landerer, R. Martinez, R. Pinto, M.I. Vera, J. Castillo, L.O. Burzio, Expression of a novel non-coding mitochondrial RNA in human proliferating cells. Nucleic Acids Res 35, 7336–7347 (2007)PubMedCrossRef

16.

V. Burzio, C. Villota, J. Villegas, E. Landerer, E. Boccardo, L.L. Villa, R. Martinez, C. Lopez, F. Gaete, V. Toro, X. Rodriguez, L.O. Burzio, Expression of a family of noncoding mitocondrial RNAs distinguishes normal from cancer cells. Proc Natl Acad Sci, USA 106, 9430–9434 (2009)PubMedCrossRef

17.

N.D. Bonawitz, D.A. Clayton, G.S. Shadel, Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol Cell 24, 813–825 (2006)PubMedCrossRef

18.

M. Falkenberg, N.G. Larsson, C.M. Gustafsson, DNA replication and transcription in mammalian mitochondria. Ann Rev Biochem 76(30), 1–30 (2007)

19.

B. Goic, J. Bustamante, A. Miquel, M. Alvarez, M.I. Vera, P.D. Valenzuela, L.O. Burzio, The nucleoprotein and the viral RNA of infectious salmon anemia virus (ISAV) are localized in the nucleolus of infected cells. Virology 379, 55–63 (2008)PubMedCrossRef

20.

S. Kobayashi, R. Amikura, M. Okada, Presence of mitochondrial large ribosomal RNA outside mitochondria in germ plasm of Drosophila melanogaster. Science 260, 1521–1524 (1993)PubMedCrossRef

21.

F.J. Iborra, D.A. Jackson, P.R. Cook, The path of RNA through nuclear pores: apparent entry from the sides into specialized pores. J Cell Sci 113, 291–302 (2000)PubMed

22.

D. Cmarko, S.O. Bøe, C. Scassellati, A.M. Szilvay, S. Davanger, X.D. Fu, G. Haukenes, K.H. Kalland, S. Fakan, Rev inhibition strongly affects intracellular distribution of human immunodeficiency virus type 1 RNAs. J Virol 76(2002), 10473–10484 (2002)PubMedCrossRef

23.

R. Gelfand, G. Attardi, Synthesis and turnover of mitochondrial ribonucleic acid in HeLa cells: the mature ribosomal and messenger ribonucleic acid species are metabolically unstable. Mol Cell Biol 1, 497–511 (1981)PubMed

24.

R.S. Puranam, G. Attardi, The RNase P associated with HeLa cell mitochondria contains an essential RNA component identical in sequence to that of the nuclear RNase P. Mol Cell Biol 21, 548–561 (2001)PubMedCrossRef

25.

G. Wang, H.W. Chen, Y. Oktay, J. Zhang, E.L. Allen, G.M. Smith, K.C. Fan, J.S. Hong, S.W. French, J.M. McCaffery, R.N. Lightowlers, H.C. Morse, C.M. Kehler, M.A. Teitell, PNPASE regulates RNA import into mitochondria. Cell 142, 456–467 (2010)PubMedCrossRef

26.

M.P. King, G. Attardi, Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 (1989)PubMedCrossRef

27.

T. Hayakawa, M. Noda, K. Yasuda, H. Yorifuji, S. Taniguchi, I. Miwa, H. Sakura, Y. Terauchi, J. Hayashi, G.W. Sharp, Y. Kanazawa, Y. Akanuma, Y. Yazaki, T. Kadowaki, Ethidium bromide-induced inhibition of mitochondrial gene transcription suppresses glucose-stimulated insulin release in the mouse pancreatic b-cell line bHC9. J Biol Chem 273, 20300–20307 (1998)PubMedCrossRef

28.

J.E. Sligh, S.E. Levy, K.G. Waymire, P. Allard, D.L. Dillehay, S. Nusinowitz, J.R. Heckenlively, G.R. MacGregor, D.C. Wallace, Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proc Natl Acad, Sci USA 97, 14461–14466 (2000)CrossRef

29.

Q. Felty, K.P. Singh, D. Roy, Estrogen-induced G1/S transition of G0 arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene 24, 4883–4893 (2005)PubMedCrossRef

30.

A. Rego, P.B. Sinclair, W. Tao, I. Kireev, A.S. Belmont, The facultative heterochromatin of the inactive X chromosome has a distinctive condensed ultrastructure. J Cell Sci 121, 1119–1127 (2008)PubMedCrossRef

31.

A. Chacinska, C.M. Koehler, D. Milenkovic, T. Lithgow, N. Pfanner, Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628–644 (2009)PubMedCrossRef

32.

D.J. Pagliarini, S.E. Calvo, B. Chang, S.A. Sheth, S.B. Vafai, S.E. Ong, G.A. Walford, C. Sugiana, A. Boneh, W.K. Chen, D.E. Hill, M. Vidal, J.G. Evans, D.R. Thorburn, S.A. Carr, V.K. Mootha, A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008)PubMedCrossRef

33.

J.D. Alfonzo, D. Söll, Mitochondrial tRNA import–the challenge to understand has just begun. Biol Chem 390, 717–722 (2009)PubMedCrossRef

34.

A. Smirnov, C. Comte, A.-M. Mager-Heckel, V. Addis, I.A. Krasheninnikov, R.P. Martin, E. Entelis, I. Tarassov, Mitochondrial enzyme rhodanese is essential for 5 S ribosomal RNA import into human mitochondria. J Biol Chem 285(2010), 30792–30803 (2010)PubMedCrossRef

35.

B.T. Kren, P.Y. Wong, A. Sarver, X. Zhang, Y. Zeng, C.J. Steer, MicroRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol 6, 65–72 (2009)PubMedCrossRef

Titel: Nuclear localization of the mitochondrial ncRNAs in normal and cancer cells
verfasst von: Eduardo Landerer
Jaime Villegas
Veronica A. Burzio
Luciana Oliveira
Claudio Villota
Constanza Lopez
Franko Restovic
Ronny Martinez
Octavio Castillo
Luis O. Burzio
Publikationsdatum: 01.08.2011
Verlag: Springer Netherlands
Erschienen in: Cellular Oncology / Ausgabe 4/2011
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-011-0018-8

Springer Medizin

Nuclear localization of the mitochondrial ncRNAs in normal and cancer cells

Abstract

Background

Methods

Results

Conclusion

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Springer Medizin

Abstract

Background

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2011

Gene expression in oligodendroglial tumors

Tumor necrosis factor-α is associated with positive lymph node status in patients with recurrence of colorectal cancer—indications for anti-TNF-α agents in cancer treatment

Dual effects of β3 integrin subunit expression on human pancreatic cancer models

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients

Rapid quantification of myocardial fibrosis: a new macro-based automated analysis

High Acute Myeloid Leukemia derived VEGFA levels are associated with a specific vascular morphology in the leukemic bone marrow

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie