Nuclear localization of the mitochondrial ncRNAs in normal and cancer cells
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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.
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.
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.
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.
KeywordsMitochondria Cancer ncRNAs Nuclear localization Retrograde signaling
We thank Mr. Alejandro Munizaga, Pontificia Universidad Catolica de Chile, for his excellent help on the electron microscopy analysis of the samples. This work was supported by Millennium Scientific Initiative N° P-77-09 F, Grants DI-34-09/R, DI-31-09/R and DI-28-09/R4, Universidad Andrés Bello, Grant D04I1338, Fondef, Grant 1085210 and Grant 11090060, Fondecyt and the CCTE-PFB16 Program, Conicyt, Chile
- 4.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)PubMedCrossRefGoogle Scholar
- 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)PubMedCrossRefGoogle Scholar
- 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)PubMedCrossRefGoogle Scholar
- 18.M. Falkenberg, N.G. Larsson, C.M. Gustafsson, DNA replication and transcription in mammalian mitochondria. Ann Rev Biochem 76(30), 1–30 (2007)Google Scholar
- 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)PubMedCrossRefGoogle Scholar
- 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)PubMedCrossRefGoogle Scholar