The Mitochondrial Unfolded Protein Response (UPR): Shielding Against Toxicity to Mitochondria in Cancer

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2022 Jul 21

PMID 35864539

Authors

Joseph R Inigo

Dhyan Chandra

Affiliations

Soon will be listed here.

Abstract

Mitochondria are essential for tumor growth and progression. However, the heavy demand for mitochondrial activity in cancer leads to increased production of mitochondrial reactive oxygen species (mtROS), accumulation of mutations in mitochondrial DNA, and development of mitochondrial dysfunction. If left unchecked, excessive mtROS can damage and unfold proteins in the mitochondria to an extent that becomes lethal to the tumor. Cellular systems have evolved to combat mtROS and alleviate mitochondrial stress through a quality control mechanism called the mitochondrial unfolded protein response (UPR). The UPR system is composed of chaperones and proteases, which promote protein folding or eliminate mitochondrial proteins damaged by mtROS, respectively. UPR is conserved and activated in cancer in response to mitochondrial stress to maintain mitochondrial integrity and support tumor growth. In this review, we discuss how mitochondria become dysfunctional in cancer and highlight the tumor-promoting functions of key components of the UPR.

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References

Schmidt O, Pfanner N, Meisinger C . Mitochondrial protein import: from proteomics to functional mechanisms. Nat Rev Mol Cell Biol. 2010; 11(9):655-67. DOI: 10.1038/nrm2959. View

Chandel N, Maltepe E, GOLDWASSER E, Mathieu C, Simon M, Schumacker P . Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. 1998; 95(20):11715-20. PMC: 21706. DOI: 10.1073/pnas.95.20.11715. View

Park S, Shin J, Jeong J, Song J, Jo Y, Kim E . Down-regulation of mortalin exacerbates Aβ-mediated mitochondrial fragmentation and dysfunction. J Biol Chem. 2013; 289(4):2195-204. PMC: 3900965. DOI: 10.1074/jbc.M113.492587. View

Kong X, Meng W, Zhou Z, Li Y, Zhou B, Wang R . Overexpression of activating transcription factor 5 in human rectal cancer. Exp Ther Med. 2012; 2(5):827-831. PMC: 3440731. DOI: 10.3892/etm.2011.295. View

Ishihara S, Yasuda M, Ishizu A, Ishikawa M, Shirato H, Haga H . Activating transcription factor 5 enhances radioresistance and malignancy in cancer cells. Oncotarget. 2015; 6(7):4602-14. PMC: 4467102. DOI: 10.18632/oncotarget.2912. View

Liu L, Lu J, Zeng H, Cai J, Zhang P, Guo X . Mortalin stabilizes CD151-depedent tetraspanin-enriched microdomains and implicates in the progression of hepatocellular carcinoma. J Cancer. 2019; 10(25):6199-6206. PMC: 6856732. DOI: 10.7150/jca.36301. View

Zhang Y, Liu Y, Liu H, Tang W . Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019; 9:19. PMC: 6377728. DOI: 10.1186/s13578-019-0282-2. View

Wadhwa R, Taira K, Kaul S . An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where?. Cell Stress Chaperones. 2002; 7(3):309-16. PMC: 514830. DOI: 10.1379/1466-1268(2002)007<0309:ahfcmm>2.0.co;2. View

Smyrnias I, Gray S, Okonko D, Sawyer G, Zoccarato A, Catibog N . Cardioprotective Effect of the Mitochondrial Unfolded Protein Response During Chronic Pressure Overload. J Am Coll Cardiol. 2019; 73(14):1795-1806. PMC: 6456800. DOI: 10.1016/j.jacc.2018.12.087. View

10.

Weydert C, Cullen J . Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc. 2010; 5(1):51-66. PMC: 2830880. DOI: 10.1038/nprot.2009.197. View

11.

Kim W, Cheon M, Kim J . Mitochondrial CCAR2/DBC1 is required for cell survival against rotenone-induced mitochondrial stress. Biochem Biophys Res Commun. 2017; 485(4):782-789. DOI: 10.1016/j.bbrc.2017.02.131. View

12.

Schulz A, Haynes C . UPR(mt)-mediated cytoprotection and organismal aging. Biochim Biophys Acta. 2015; 1847(11):1448-56. PMC: 4575829. DOI: 10.1016/j.bbabio.2015.03.008. View

13.

Liu Z, Butow R . Mitochondrial retrograde signaling. Annu Rev Genet. 2006; 40:159-85. DOI: 10.1146/annurev.genet.40.110405.090613. View

14.

Neher S, Sauer R, Baker T . Distinct peptide signals in the UmuD and UmuD' subunits of UmuD/D' mediate tethering and substrate processing by the ClpXP protease. Proc Natl Acad Sci U S A. 2003; 100(23):13219-24. PMC: 263758. DOI: 10.1073/pnas.2235804100. View

15.

Zhou Z, Ribas V, Rajbhandari P, Drew B, Moore T, Fluitt A . Estrogen receptor α protects pancreatic β-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J Biol Chem. 2018; 293(13):4735-4751. PMC: 5880140. DOI: 10.1074/jbc.M117.805069. View

16.

Hartwell L, Szankasi P, Roberts C, Murray A, Friend S . Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997; 278(5340):1064-8. DOI: 10.1126/science.278.5340.1064. View

17.

Piselli P, Vendetti S, Vismara D, Cicconi R, Poccia F, Colizzi V . Different expression of CD44, ICAM-1, and HSP60 on primary tumor and metastases of a human pancreatic carcinoma growing in scid mice. Anticancer Res. 2000; 20(2A):825-31. View

18.

Kuhlbrandt W . Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015; 13:89. PMC: 4625866. DOI: 10.1186/s12915-015-0201-x. View

19.

Cappello F, Rappa F, David S, Anzalone R, Zummo G . Immunohistochemical evaluation of PCNA, p53, HSP60, HSP10 and MUC-2 presence and expression in prostate carcinogenesis. Anticancer Res. 2003; 23(2B):1325-31. View

20.

van der Bliek A, Sedensky M, Morgan P . Cell Biology of the Mitochondrion. Genetics. 2017; 207(3):843-871. PMC: 5676242. DOI: 10.1534/genetics.117.300262. View