Mitochondrion-processed TERC regulates senescence without affecting telomerase activities
Received date: 28 Oct 2018
Accepted date: 15 Jan 2019
Published date: 15 Sep 2019
Copyright
Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERCis imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. Cytosolic TERC-53levels respond to mito- chondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53functions downstream of mitochondria as a signal of mitochon- drial functions. Here, we show that cytosolic TERC-53plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53levels affects cellular senescence and cognition decline in 10 months old mouse hip-pocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc−/− cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals.
Key words: mitochondria; retrograde signal; nucleus; transcription regulation; non-coding RNA; telomerase
Qian Zheng , Peipei Liu , Ge Gao , Jiapei Yuan , Pengfeng Wang , Jinliang Huang , Leiming Xie , Xinping Lu , Fan Di , Tanjun Tong , Jun Chen , Zhi Lu , Jisong Guan , Geng Wang . Mitochondrion-processed TERC regulates senescence without affecting telomerase activities[J]. Protein & Cell, 2019 , 10(9) : 631 -648 . DOI: 10.1007/s13238-019-0612-5
1 |
Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L
|
2 |
Alfonzo JD, Soll D (2009) Mitochondrial tRNA import–the challenge to understand has just begun. Biol Chem 390:717–722
|
3 |
Azam S, Jouvet N, Jilani A, Vongsamphanh R, Yang X, Yang S, Ramotar D (2008) Human glyceraldehyde-3-phosphate dehydro- genase plays a direct role in reactivating oxidized forms of the DNA repair enzyme APE1. J Biol Chem 283:30632–30641
|
4 |
Bernardes de Jesus B, Blasco MA (2013) Telomerase at the intersection of cancer and aging. Trends Genet 29:513–520
|
5 |
Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535
|
6 |
Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:25–34
|
7 |
Cawthon RM (2009) Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res 37:e21
|
8 |
Chang C, Su H, Zhang D, Wang Y, Shen Q, Liu B, Huang R, Zhou T, Peng C, Wong CC
|
9 |
Chang DD, Clayton DA (1989) Mouse RNAase MRP RNA is encoded by a nuclear gene and contains a decamer sequence complementary to a conserved region of mitochondrial RNA substrate. Cell 56:131–139
|
10 |
Chen HW, Rainey RN, Balatoni CE, Dawson DW, Troke JJ, Wasiak S, Hong JS, McBride HM, Koehler CM, Teitell MA
|
11 |
Cheng Y, Liu P, Zheng Q, Gao G, Yuan J, Wang P, Huang J, Xie L, Lu X, Tong T
|
12 |
Chuang DM, Ishitani R (1996) A role for GAPDH in apoptosis and neurodegeneration. Nat Med 2:609–610
|
13 |
Coates PJ, Jamieson DJ, Smart K, Prescott AR, Hall PA (1997) The prohibitin family of mitochondrial proteins regulate replicative lifespan. Curr Biol 7:607–610
|
14 |
Feng J, Meyer CA, Wang Q, Liu JS, Shirley Liu X, Zhang Y (2012) GFOLD: a generalized fold change for ranking differentially expressed genes from RNA-seq data. Bioinformatics 28:2782–2788
|
15 |
Gall JG (1990) Telomerase RNA: tying up the loose ends. Nature 344:108–109
|
16 |
Gottlieb RA, Bernstein D (2016) Mitochondrial remodeling: rear- ranging, recycling, and reprogramming. Cell Calcium 60:88–101
|
17 |
Guha M, Avadhani NG (2013) Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion 13:577–591
|
18 |
Hachiya N, Alam R, Sakasegawa Y, Sakaguchi M, Mihara K, Omura T (1993) A mitochondrial import factor purified from rat liver cytosol is an ATP-dependent conformational modulator for precursor proteins. EMBO J 12:1579–1586
|
19 |
Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah JH, Tankou SK, Hester LD
|
20 |
Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadinanos J
|
21 |
Jozefczuk J, Drews K, Adjaye J (2012) Preparation of mouse embryonic fibroblast cells suitable for culturing human embryonic and induced pluripotent stem cells. J Vis Exp. https://doi.org/10.3791/3854
|
22 |
Kotiadis VN, Duchen MR, Osellame LD (2014) Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochim Biophys Acta 1840:1254–1265
|
23 |
Li N, Li Q, Cao X, Zhao G, Xue L, Tong T (2011) The tumor suppressor p33ING1b upregulates p16INK4a expression and induces cellular senescence. FEBS Lett 585:3106–3112
|
24 |
Liu P, Huang J, Zheng Q, Xie L, Lu X, Jin J, Wang G (2017) Mammalian mitochondrial RNAs are degraded in the mitochon- drial intermembrane space by RNASET2. Protein Cell 8:735–749
|
25 |
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217
|
26 |
Lopez-Otin C, Galluzzi L, Freije JM, Madeo F, Kroemer G (2016) Metabolic control of longevity. Cell 166:802–821
|
27 |
Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891
|
28 |
McAvoy KM, Scobie KN, Berger S, Russo C, Guo N, Decharatanachart P, Vega-Ramirez H, Miake-Lye S, Whalen M, Nelson M
|
29 |
Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood AM, Haugen E, Bracken CP, Rackham O, Stamatoyannopoulos JA
|
30 |
Min B, Park M, Jeon K, Park JS, Seo H, Jeong S, Kang YK (2018) Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription. Aging 10:789–807
|
31 |
Nagy E, Henics T, Eckert M, Miseta A, Lightowlers RN, Kellermayer M (2000) Identification of the NAD(+)-binding fold of glyceralde-hyde-3-phosphate dehydrogenase as a novel RNA-binding domain. Biochem Biophys Res Commun 275:253–260
|
32 |
Nicholls C, Pinto AR, Li H, Li L, Wang L, Simpson R, Liu JP (2012) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component. Proc Natl Acad Sci USA 109:13308–13313
|
33 |
Phadke M, Krynetskaia N, Mishra A, Krynetskiy E (2011) Acceler-ated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells. Biochem Biophys Res Commun 411:409–415
|
34 |
Reczek CR, Chandel NS (2015) ROS-dependent signal transduction. Curr Opin Cell Biol 33:8–13
|
35 |
Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96:701–712
|
36 |
Sarkar D, Leszczyniecka M, Kang DC, Lebedeva IV, Valerie K, Dhar S, Pandita TK, Fisher PB (2003) Down-regulation of Myc as a potential target for growth arrest induced by human polynu-cleotide phosphorylase (hPNPaseold-35) in human melanoma cells. J Biol Chem 278:24542–24551
|
37 |
Sato R, Arai-Ichinoi N, Kikuchi A, Matsuhashi T, Numata-Uematsu Y, Uematsu M, Fujii Y, Murayama K, Ohtake A, Abe T
|
38 |
Sawa A, Khan AA, Hester LD, Snyder SH (1997) Glyceraldehyde-3-phosphate dehydrogenase: nuclear translocation participates in neuronal and nonneuronal cell death. Proc Natl Acad Sci USA 94:11669–11674
|
39 |
Schulz AM, Haynes CM (2015) UPR(mt)-mediated cytoprotection and organismal aging. Biochim Biophys Acta 1847:1448–1456
|
40 |
Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N, Thomas B, Dawson TM, Dawson VL, Snyder SH
|
41 |
Sullivan LB, Chandel NS (2014) Mitochondrial reactive oxygen species and cancer. Cancer Metab 2:17
|
42 |
Sun N, Youle RJ, Finkel T (2016) The mitochondrial basis of aging. Mol Cell 61:654–666
|
43 |
Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, Pimentel H, Salzberg SL, Rinn JL, Pachter L (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7:562–578
|
44 |
Vedrenne V, Gowher A, De Lonlay P, Nitschke P, Serre V, Boddaert N, Altuzarra C, Mager-Heckel AM, Chretien F, Entelis N
|
45 |
von Ameln S, Wang G, Boulouiz R, Rutherford MA, Smith GM, Li Y, Pogoda HM, Nurnberg G, Stiller B, Volk AE
|
46 |
Wallace DC (2012) Mitochondria and cancer. Nature reviews. Cancer 12:685–698
|
47 |
Wang G, Chen HW, Oktay Y, Zhang J, Allen EL, Smith GM, Fan KC, Hong JS, French SW, McCaffery JM
|
48 |
Yee C, Yang W, Hekimi S (2014) The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell 157:897–909
|
49 |
Zhang X, Zuo X, Yang B, Li Z, Xue Y, Zhou Y, Huang J, Zhao X, Zhou J, Yan Y
|
/
〈 | 〉 |