182:
targeting sequence (MTS) that allows for import into the mitochondria. In healthy cells, ATFS-1 is preferentially targeted to the mitochondrial matrix where it is degraded by the Lon protease. The MTS on ATFS-1 is predicted by
Mitofates to be substantially weaker than most MTSs which would allow it to be sensitive to subtle mitochondrial dysfunction. Following mitochondrial stress, ATFS-1 mitochondrial import efficiency is decreased resulting in a cytoplasmic accumulation of ATFS-1. Subsequently, ATFS-1 will enter the nucleus via its nuclear transport signal. In the nucleus, ATFS-1 has a broad transcriptional regulation as it will: attenuate OXPHOS gene expression in both the nucleus and mitochondria, upregulate chaperones and proteases to re-establish mitochondrial proteostasis, increase ROS detoxification, and increase mitochondrial import machinery.
146:
proteins and restore homeostasis. Despite their names, the two pathways possess distinct initiating stimuli and signaling mechanisms that regulate the responses. The ER UPR is induced by a variety of cellular stressors that inhibit protein folding or exit of the ER. Within the ER GRP78, an ER lumen chaperone, is bound to ER membrane proteins. When unfolded proteins build up, it dissociates to from the membrane to aid in protein folding. GRP78 dissociation triggers the UPR that restores protein homeostasis via three pathways (IRE1, PERK, and
169:; ATF5 in mammals). AFTS-1 is usually imported into the mitochondria where it is degraded by the LON protease. Mitochondrial dysfunction inhibits this process and allows ATFS-1 to accumulate in the cytosol and enter the nucleus where it can act as a transcription factor. This responses restores proteostasis by upregulating chaperones and proteases, increasing reactive oxygen species (ROS) detoxification, and increasing mitochondrial import machinery.
181:
The appropriately named activating transcription factor associated with stress (ATFS-1) is one of the primary transcription factors required for UPR activation in worms. ATFS-1 has a nuclear localization sequence that allows it to be imported into the nucleus as well as an N-terminal mitochondrial
145:
In organelles like the ER and mitochondria, the response is slightly more complex. Both UPR mechanisms are conceptually similar in that they are activated by the accumulation of misfolded/ unfolded proteins and induce the translational upregulation of molecular chaperones and proteases to process
177:
In mammals, UPR has mostly been studied using transfection with a truncated, dysfunctional mitochondrial enzyme (OTCΔ) that does not fold correctly after translocation into the mitochondrial matrix. Using this approach, several components of the mammalian UPR have been identified including the
211:
Inflammatory bowel diseases (Crohn´s disease and ulcerative colitis) have been associated with mitochondrial dysfunction in the intestinal epithelium. In mouse models of intestinal inflammation and in IBD patients, signs of UPR -activation have been demonstrated. In particular, mitochondrial
194:
axis of UPR as a marker to differentiate between metastatic and non-metastatic breast cancer. As many cancers exhibit a metabolic shift from oxidative phosporylation-depentent energy production to aerobic glycolysis dependent energy production, also known as the
457:
Bar-Ziv, Raz; Dutta, Naibedya; Hruby, Adam; Sukarto, Edward; Averbukh, Maxim; Alcala, Athena; Henderson, Hope R.; Durieux, Jenni; Tronnes, Sarah U.; Ahmad, Qazi; Bolas, Theodore; Perez, Joel; Dishart, Julian G.; Vega, Matthew; Garcia, Gilberto (2023-10-13).
178:
mitochondrial chaperone heat shock protein 60 (Hsp60), the mitochondrial caseinolytic peptidase ClpP, the transcription factor Chop and the kinases c-Jun N-terminal kinase (JNK) and the interferon-induced, double-stranded RNA-activated protein kinase (Pkr).
128:
also must be folded to function. Consequently, specific cellular mechanisms exist that aim to detect cellular stress (causing misfolded/unfolded proteins to accumulate), transduce the signal to the nucleus, and mediate the restoration of protein homeostasis
523:
Shen, Koning; Durieux, Jenni; Mena, Cesar G.; Webster, Brant M.; Kimberly Tsui, C.; Zhang, Hanlin; Joe, Lawrence; Berendzen, Kristen; Dillin, Andrew (2023-08-22). The germline coordinates mitokine signaling (Report). Genetics.
110:
mitochondria has been found to play a significant role in the signalling and regulation of UPR have been shown to play a central role
Nicotinamide riboside supplementation in mice has also been shown to activate the UPR.
137:
is a transcription factor that, upon increases in unfolded cytosolic proteins, will trimerize and enter the nucleus to upregulate the expression of heat shock proteins (HSPs) that will act as protein folding
119:
A majority of cellular proteins are translated and folded in the cytosol with the help of molecular chaperones. Just as proteins must be folded to function in the cytosol, proteins in organelles like the
150:). The UPR restores proteostasis by selectively attenuation protein translation, upregulating protein folding chaperones, and degrading excess misfolded proteins via ER associated protein degradation (
1214:
Hu M, Wang B, Qian D, Li L, Zhang L, Song X, Liu DX (October 2012). "Interference with ATF5 function enhances the sensitivity of human pancreatic cancer cells to paclitaxel-induced apoptosis".
151:
199:, researchers suggest that cancer cells rely on the UPR to maintain the mitochondrial integrity. Furthermore, multiple studies have shown that inhibition of UPR, specifically
1113:"The Mitochondrial Unfolded Protein Response as a Non-Oncogene Addiction to Support Adaptation to Stress during Transformation in Cancer and Beyond"
964:"Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation"
1287:"Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn's disease recurrence"
91:
562:
793:
Shpilka T, Haynes CM (February 2018). "The mitochondrial UPR: mechanisms, physiological functions and implications in ageing".
49:
190:
Recent research has implicated the UPR in the transformation of cells in to cancer cells. Researchers have identified the
636:"The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease"
45:
1404:
841:"Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements"
133:). In the cytosol, the heat shock response (HSR) manages the unfolded proteins through heat shock factor 1 (HSF1).
737:
Walter P, Ron D (November 2011). "The unfolded protein response: from stress pathway to homeostatic regulation".
221:
196:
75:
25:
900:"The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response"
410:"The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling"
83:
212:
dysfunction and UPR -activation have been linked to intestinal stemness and Paneth cell (dys-)function.
1399:
121:
99:
1349:
1243:"Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5"
911:
852:
746:
593:
471:
41:
139:
37:
1285:
Khaloian S, Rath E, Hammoudi N, Gleisinger E, Blutke A, Giesbertz P, et al. (February 2020).
818:
770:
1409:
1375:
1318:
1264:
1223:
1196:
1144:
1093:
1044:
1013:"MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites"
993:
939:
880:
810:
762:
719:
665:
611:
543:
505:
487:
439:
390:
341:
292:
226:
79:
1336:
Berger E, Rath E, Yuan D, Waldschmitt N, Khaloian S, Allgäuer M, et al. (October 2016).
1064:"mt regulation and output: a stress response mediated by mitochondrial-nuclear communication"
582:"NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice"
408:
Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, et al. (July 2013).
1365:
1357:
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Angelastro JM, Canoll PD, Kuo J, Weicker M, Costa A, Bruce JN, Greene LA (February 2006).
33:
1353:
1167:"Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR"
915:
856:
750:
597:
538:
500:
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459:
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409:
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262:
1393:
125:
1182:
822:
90:
worms) also activate the UPR. Activation of the UPR in nematode worms by increasing
962:
Rath E, Berger E, Messlik A, Nunes T, Liu B, Kim SC, et al. (September 2012).
130:
95:
29:
1338:"Mitochondrial function controls intestinal epithelial stemness and proliferation"
774:
924:
865:
278:
162:
64:
1303:
979:
425:
376:
361:"The cell-non-autonomous nature of electron transport chain-mediated longevity"
529:
491:
203:, selectively kills human and rat cancer cells rather than non-cancer cells.
1129:
1029:
758:
704:
688:"The mitochondrial unfolded protein response: Signaling from the powerhouse"
606:
581:
460:"Glial-derived mitochondrial signals affect neuronal proteostasis and aging"
191:
155:
107:
68:
1379:
1322:
1268:
1259:
1242:
1227:
1200:
1148:
1097:
1048:
997:
943:
884:
814:
766:
723:
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615:
547:
509:
483:
443:
394:
345:
296:
580:
Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, et al. (June 2016).
806:
327:
87:
53:
1361:
1079:
651:
57:
1011:
Fukasawa Y, Tsuji J, Fu SC, Tomii K, Horton P, Imai K (April 2015).
236:
231:
60:
200:
147:
134:
103:
56:
to degrade proteins that fail to fold properly. UPR causes the
312:"SirT3 regulates the mitochondrial unfolded protein response"
267:
Biochimica et
Biophysica Acta (BBA) - Molecular Cell Research
36:
or misfolded proteins in mitochondria beyond the capacity of
839:
Aldridge JE, Horibe T, Hoogenraad NJ (September 2007).
263:"Signaling the mitochondrial unfolded protein response"
563:"Cells Across the Body Talk to Each Other About Aging"
261:
Pellegrino MW, Nargund AM, Haynes CM (February 2013).
634:
Jovaisaite V, Mouchiroud L, Auwerx J (January 2014).
686:
Qureshi MA, Haynes CM, Pellegrino MW (August 2017).
154:). Prolonged activation of the UPR can result in
834:
832:
40:to handle them. The UPR can occur either in the
1111:Kenny TC, Manfredi G, Germain D (2017-07-26).
256:
254:
252:
359:Durieux J, Wolff S, Dillin A (January 2011).
8:
48:. In the UPR, the mitochondrion will either
898:Horibe T, Hoogenraad NJ (September 2007).
207:Relationship to inflammatory bowel disease
1369:
1312:
1302:
1258:
1190:
1138:
1128:
1087:
1038:
1028:
987:
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713:
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659:
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384:
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18:mitochondrial unfolded protein response
795:Nature Reviews. Molecular Cell Biology
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953:
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786:
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681:
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7:
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625:
1165:Deng P, Haynes CM (December 2017).
1017:Molecular & Cellular Proteomics
692:The Journal of Biological Chemistry
640:The Journal of Experimental Biology
310:Papa L, Germain D (February 2014).
115:Cellular unfolded protein responses
102:has been shown to extend lifespan.
1062:Melber A, Haynes CM (March 2018).
14:
165:transcription factor ATFS-1 (in
1183:10.1016/j.semcancer.2017.05.002
561:Callier, Viviane (2024-01-08).
161:The UPR progresses through the
316:Molecular and Cellular Biology
1:
52:chaperone proteins or invoke
925:10.1371/journal.pone.0000835
866:10.1371/journal.pone.0000874
279:10.1016/j.bbamcr.2012.02.019
46:mitochondrial inner membrane
1426:
1304:10.1136/gutjnl-2019-319514
1171:Seminars in Cancer Biology
980:10.1136/gutjnl-2011-300767
426:10.1016/j.cell.2013.06.016
377:10.1016/j.cell.2010.12.016
78:mutations that extend the
530:10.1101/2023.08.21.554217
222:Unfolded protein response
94:by supplementation with
76:electron transport chain
26:cellular stress response
1130:10.3389/fonc.2017.00159
1030:10.1074/mcp.M114.043083
759:10.1126/science.1209038
705:10.1074/jbc.R117.791061
607:10.1126/science.aaf2693
32:. The UPR results from
1260:10.1038/sj.onc.1209116
484:10.1126/sciadv.adi1411
186:Relationship to cancer
84:Caenorhabditis elegans
1342:Nature Communications
1117:Frontiers in Oncology
122:endoplasmic reticulum
100:nicotinamide riboside
807:10.1038/nrm.2017.110
328:10.1128/MCB.01337-13
42:mitochondrial matrix
1362:10.1038/ncomms13171
1354:2016NatCo...713171B
1216:Anticancer Research
916:2007PLoSO...2..835H
857:2007PLoSO...2..874A
751:2011Sci...334.1081W
698:(33): 13500–13506.
598:2016Sci...352.1436Z
476:2023SciA....9I1411B
65:antioxidant enzymes
1080:10.1038/cr.2018.16
652:10.1242/jeb.090738
38:chaperone proteins
1405:Molecular biology
1297:(11): 1939–1951.
592:(6292): 1436–43.
227:Genetics of aging
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974:(9): 1269–1278.
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878:
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827:
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745:(6059): 1081–6.
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683:
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646:(Pt 1): 137–43.
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470:(41): eadi1411.
464:Science Advances
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1222:(10): 4385–94.
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567:Quanta Magazine
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28:related to the
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1402:
1392:
1391:
1386:
1385:
1328:
1274:
1233:
1206:
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1103:
1074:(3): 281–295.
1054:
1023:(4): 1113–26.
1003:
949:
890:
828:
801:(2): 109–120.
780:
729:
675:
621:
572:
553:
515:
449:
400:
351:
322:(4): 699–710.
302:
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197:Warburg effect
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74:Mitochondrial
13:
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2:
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1253:(6): 907–16.
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1068:Cell Research
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420:(2): 430–41.
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1400:Mitochondria
1348:(1): 13171.
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371:(1): 79–91.
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273:(2): 410–6.
270:
266:
210:
189:
180:
176:
166:
160:
144:
131:proteostasis
126:mitochondria
118:
96:nicotinamide
73:
63:to activate
30:mitochondria
21:
17:
15:
910:(9): e835.
851:(9): e874.
1394:Categories
243:References
167:C. elegans
140:chaperones
50:upregulate
44:or in the
1177:: 43–49.
492:2375-2548
173:Molecular
156:apoptosis
124:(ER) and
80:life span
69:mitophagy
54:proteases
1410:Proteins
1380:27786175
1323:32111634
1269:16170340
1247:Oncogene
1228:23060563
1201:28499833
1149:28798902
1098:29424373
1049:25670805
998:21997551
944:17848986
904:PLOS ONE
885:17849004
845:PLOS ONE
823:20063954
815:29165426
767:22116877
724:28687630
670:24353213
616:27127236
548:37873079
539:10592821
510:37831769
501:10575585
444:23870130
395:21215371
346:24324009
297:22445420
216:See also
108:germline
88:nematode
34:unfolded
1371:5080445
1350:Bibcode
1314:7569388
1192:5681445
1140:5526845
1123:: 159.
1089:5835775
1040:4390256
989:4514769
935:1950685
912:Bibcode
876:1964532
853:Bibcode
747:Bibcode
739:Science
715:5566509
661:3867496
594:Bibcode
586:Science
472:Bibcode
435:3062502
386:3753670
337:3911493
288:3393825
58:sirtuin
24:) is a
1378:
1368:
1321:
1311:
1267:
1226:
1199:
1189:
1147:
1137:
1096:
1086:
1047:
1037:
996:
986:
942:
932:
883:
873:
821:
813:
775:691563
773:
765:
722:
712:
668:
658:
614:
546:
536:
508:
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442:
432:
393:
383:
344:
334:
295:
285:
819:S2CID
771:S2CID
237:Age-1
232:Daf-2
192:SIRT3
135:HSF-1
104:Glial
61:SIRT3
1376:PMID
1319:PMID
1265:PMID
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