The mitochondrial unfolded protein response (UPRmt) is a cellular stress response related to the mitochondria. The UPRmt results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them.[1] The UPRmt can occur either in the mitochondrial matrix or in the mitochondrial inner membrane.[1] In the UPRmt, the mitochondrion will either upregulate chaperone proteins or invoke proteases to degrade proteins that fail to fold properly.[1] UPRmt causes the sirtuin SIRT3 to activate antioxidant enzymes and mitophagy.[2]

Mitochondrial electron transport chain mutations that extend the life span of Caenorhabditis elegans (nematode worms) also activate the UPRmt.[3] Activation of the UPRmt in nematode worms by increasing NAD+ by supplementation with nicotinamide or nicotinamide riboside has been shown to extend lifespan.[4] Glial and germline mitochondria has been found to play a significant role in the signalling and regulation of UPRmt[5][6][7] have been shown to play a central role Nicotinamide riboside supplementation in mice has also been shown to activate the UPRmt.[8]

Cellular unfolded protein responses

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 endoplasmic reticulum (ER) and mitochondria 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 (proteostasis). In the cytosol, the heat shock response (HSR) manages the unfolded proteins through heat shock factor 1 (HSF1). HSF-1 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 chaperones.[9]

In organelles like the ER and mitochondria, the responses 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 proteins and restore homeostasis.[10]  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 UPRER that restores protein homeostasis via three pathways (IRE1, PERK, and ATF6).[11] The UPRER restores proteostasis by selectively attenuation protein translation, upregulating protein folding chaperones, and degrading excess misfolded proteins via ER associated protein degradation (ERAD). Prolonged activation of the UPRER can result in apoptosis.[9]

The UPRmt progresses through the bZIP transcription factor ATFS-1 (in C. elegans; 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.[12][9]

Molecular

In mammals, UPRmt has mostly been studied using transfection with a truncated, dysfunctional mitochondrial enzyme (OTCΔ) that does not fold correctly after translocation into the mitochondrial matrix.[13] Using this approach, several components of the mammalian UPRmt have been identified including the 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).[13][14][15]

The appropriately named activating transcription factor associated with stress (ATFS-1) is one of the primary transcription factors required for UPRmt 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 targeting sequence (MTS) that allows for import into the mitochondria.[12]  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[16] to be substantially weaker than most MTSs which would allow it to be sensitive to subtle mitochondrial dysfunction.[17] 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.[10][12]

Relationship to cancer

Recent research has implicated the UPRmt in the transformation of cells in to cancer cells. Researchers have identified the SIRT3 axis of UPRmt as a marker to differentiate between metastatic and non-metastatic breast cancer.[18] As many cancers exhibit a metabolic shift from oxidative phosporylation-depentent energy production to aerobic glycolysis dependent energy production, also known as the Warburg effect, researchers suggest that cancer cells rely on the UPRmt to maintain the mitochondrial integrity.[19] Furthermore, multiple studies have shown that inhibition of UPRmt, specifically ATF5, selectively kills human and rat cancer cells rather than non-cancer cells.[19][20][21]

Relationship to inflammatory bowel disease

Inflammatory bowel diseases (Crohn´s disease and ulcerative colitis) have been associated with mitochondrial dysfunction in the intestinal epithelium.[15] In mouse models of intestinal inflammation and in IBD patients, signs of UPRmt -activation have been demonstrated.[15][22] In particular, mitochondrial dysfunction and UPRmt -activation have been linked to intestinal stemness and Paneth cell (dys-)function.[22][23]

See also

References

  1. 1 2 3 Pellegrino MW, Nargund AM, Haynes CM (February 2013). "Signaling the mitochondrial unfolded protein response". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (2): 410–6. doi:10.1016/j.bbamcr.2012.02.019. PMC 3393825. PMID 22445420.
  2. ↑ Papa L, Germain D (February 2014). "SirT3 regulates the mitochondrial unfolded protein response". Molecular and Cellular Biology. 34 (4): 699–710. doi:10.1128/MCB.01337-13. PMC 3911493. PMID 24324009.
  3. ↑ Durieux J, Wolff S, Dillin A (January 2011). "The cell-non-autonomous nature of electron transport chain-mediated longevity". Cell. 144 (1): 79–91. doi:10.1016/j.cell.2010.12.016. PMC 3753670. PMID 21215371.
  4. ↑ Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, et al. (July 2013). "The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling". Cell. 154 (2): 430–41. doi:10.1016/j.cell.2013.06.016. PMC 3062502. PMID 23870130.
  5. ↑ 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). "Glial-derived mitochondrial signals affect neuronal proteostasis and aging". Science Advances. 9 (41). doi:10.1126/sciadv.adi1411. ISSN 2375-2548. PMC 10575585. PMID 37831769.
  6. ↑ 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. doi:10.1101/2023.08.21.554217. PMC 10592821. PMID 37873079.
  7. ↑ Callier, Viviane (2024-01-08). "Cells Across the Body Talk to Each Other About Aging". Quanta Magazine.
  8. ↑ Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, et al. (June 2016). "NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice". Science. 352 (6292): 1436–43. Bibcode:2016Sci...352.1436Z. doi:10.1126/science.aaf2693. PMID 27127236.
  9. 1 2 3 Jovaisaite V, Mouchiroud L, Auwerx J (January 2014). "The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease". The Journal of Experimental Biology. 217 (Pt 1): 137–43. doi:10.1242/jeb.090738. PMC 3867496. PMID 24353213.
  10. 1 2 Qureshi MA, Haynes CM, Pellegrino MW (August 2017). "The mitochondrial unfolded protein response: Signaling from the powerhouse". The Journal of Biological Chemistry. 292 (33): 13500–13506. doi:10.1074/jbc.R117.791061. PMC 5566509. PMID 28687630.
  11. ↑ Walter P, Ron D (November 2011). "The unfolded protein response: from stress pathway to homeostatic regulation". Science. 334 (6059): 1081–6. Bibcode:2011Sci...334.1081W. doi:10.1126/science.1209038. PMID 22116877. S2CID 691563.
  12. 1 2 3 Shpilka T, Haynes CM (February 2018). "The mitochondrial UPR: mechanisms, physiological functions and implications in ageing". Nature Reviews. Molecular Cell Biology. 19 (2): 109–120. doi:10.1038/nrm.2017.110. PMID 29165426. S2CID 20063954.
  13. 1 2 Aldridge JE, Horibe T, Hoogenraad NJ (September 2007). "Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements". PLOS ONE. 2 (9): e874. Bibcode:2007PLoSO...2..874A. doi:10.1371/journal.pone.0000874. PMC 1964532. PMID 17849004.
  14. ↑ Horibe T, Hoogenraad NJ (September 2007). "The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response". PLOS ONE. 2 (9): e835. Bibcode:2007PLoSO...2..835H. doi:10.1371/journal.pone.0000835. PMC 1950685. PMID 17848986.
  15. 1 2 3 Rath E, Berger E, Messlik A, Nunes T, Liu B, Kim SC, et al. (September 2012). "Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation". Gut. 61 (9): 1269–1278. doi:10.1136/gutjnl-2011-300767. PMC 4514769. PMID 21997551.
  16. ↑ Fukasawa Y, Tsuji J, Fu SC, Tomii K, Horton P, Imai K (April 2015). "MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites". Molecular & Cellular Proteomics. 14 (4): 1113–26. doi:10.1074/mcp.M114.043083. PMC 4390256. PMID 25670805.
  17. ↑ Melber A, Haynes CM (March 2018). "mt regulation and output: a stress response mediated by mitochondrial-nuclear communication". Cell Research. 28 (3): 281–295. doi:10.1038/cr.2018.16. PMC 5835775. PMID 29424373.
  18. ↑ Kenny TC, Manfredi G, Germain D (2017-07-26). "The Mitochondrial Unfolded Protein Response as a Non-Oncogene Addiction to Support Adaptation to Stress during Transformation in Cancer and Beyond". Frontiers in Oncology. 7: 159. doi:10.3389/fonc.2017.00159. PMC 5526845. PMID 28798902.
  19. 1 2 Deng P, Haynes CM (December 2017). "Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR". Seminars in Cancer Biology. 47: 43–49. doi:10.1016/j.semcancer.2017.05.002. PMC 5681445. PMID 28499833.
  20. ↑ 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". Anticancer Research. 32 (10): 4385–94. PMID 23060563.
  21. ↑ Angelastro JM, Canoll PD, Kuo J, Weicker M, Costa A, Bruce JN, Greene LA (February 2006). "Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5". Oncogene. 25 (6): 907–16. doi:10.1038/sj.onc.1209116. PMID 16170340.
  22. 1 2 Khaloian S, Rath E, Hammoudi N, Gleisinger E, Blutke A, Giesbertz P, et al. (February 2020). "Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn's disease recurrence". Gut. 69 (11): 1939–1951. doi:10.1136/gutjnl-2019-319514. PMC 7569388. PMID 32111634.
  23. ↑ Berger E, Rath E, Yuan D, Waldschmitt N, Khaloian S, Allgäuer M, et al. (October 2016). "Mitochondrial function controls intestinal epithelial stemness and proliferation". Nature Communications. 7 (1): 13171. Bibcode:2016NatCo...713171B. doi:10.1038/ncomms13171. PMC 5080445. PMID 27786175.
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