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From discovery of the CHOP axis and targeting ClpP to the identification of additional axes of the UPRmt driven by the estrogen receptor and SIRT3

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Abstract

The mitochondrial UPR (UPRmt) is rapidly gaining attention. While most studies on the UPRmt have focused on its role in aging, emerging studies suggest an important role of the UPRmt in cancer. Further, several of the players of the UPRmt in mammalian cells have well reported roles in the maintenance of the organelle. The goal of this review is to emphasize aspects of the UPRmt that have been overlooked in the current literature, describe the role of specific players of the UPRmt in the biology of the mitochondria and highlight the intriguing possibility that targeting the UPRmt in cancer may be already within reach.

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References

  • Arnold I, Langer T (2002) Membrane protein degradation by AAA proteases in mitochondria. Biochim Biophys Acta, Mol Cell Res 1592:89–96. doi:10.1016/S0167-4889(02)00267-7

    Article  CAS  Google Scholar 

  • Ashraf N, Zino S, MacIntyre A et al (2006) Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer 95:1056–1061. doi:10.1038/sj.bjc.6603384

    Article  CAS  Google Scholar 

  • Bernstein SH, Venkatesh S, Li M et al (2012) The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood 119:3321–3329. doi:10.1182/blood-2011-02

    Article  CAS  Google Scholar 

  • Bhat-Nakshatri P, Wang G, Appaiah H et al (2008) AKT Alters Genome-Wide Estrogen Receptor Binding and Impacts Estrogen Signaling in Breast Cancer. Mol Cell Biol 28:7487–7503. doi:10.1128/MCB.00799-08

    Article  CAS  Google Scholar 

  • Bota DA, Van Remmen H, Davies KJA (2002) Modulation of Lon protease activity and aconitase turnover during aging and oxidative stress. FEBS Lett 532:103–106. doi:10.1016/S0014-5793(02)03638-4

    Article  CAS  Google Scholar 

  • Campbell RA, Bhat-Nakshatri P, Patel NM et al (2001) Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α. J Biol Chem 276:9817–9824. doi:10.1074/jbc.M010840200

    Article  CAS  Google Scholar 

  • Carroll JS, Meyer CA, Song J et al (2006) Genome-wide analysis of estrogen receptor binding sites. Nat Genet 38:1289–1297. doi:10.1038/ng1901

    Article  CAS  Google Scholar 

  • Chae YC, Angelin A, Lisanti S et al (2013) Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun 4:2139. doi:10.1038/ncomms3139

    Article  Google Scholar 

  • Cole A, Wang Z, Coyaud E et al (2015) Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer Cell 27:864–876. doi:10.1016/j.ccell.2015.05.004

    Article  CAS  Google Scholar 

  • Cruz-Bermúdez A, Vallejo CG, Vicente-Blanco RJ et al (2015) Enhanced tumorigenicity by mitochondrial DNA mild mutations. Oncotarget 6:13628–13643. doi:10.18632/oncotarget.3698

    Article  Google Scholar 

  • Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144:79–91. doi:10.1016/j.cell.2010.12.016

    Article  CAS  Google Scholar 

  • Feeley KP, Bray AW, Westbrook DG et al (2015) Mitochondrial genetics regulate breast cancer tumorigenicity and metastatic potential HHS Public Access. Cancer Res 75:4429–4436. doi:10.1158/0008-5472.CAN-15-0074

    Article  CAS  Google Scholar 

  • Finley LWS, Carracedo A, Lee J et al (2011) SIRT3 Opposes Reprogramming of Cancer Cell Metabolism through HIF1α Destabilization. Cancer Cell 19:416–428. doi:10.1016/j.ccr.2011.02.014

    Article  CAS  Google Scholar 

  • Franco HL, Nagari A, Lee W, Correspondence K (2015) TNFα Signaling Exposes Latent Estrogen Receptor Binding Sites to Alter the Breast Cancer Cell Transcriptome. Mol Cell 58:21–34. doi:10.1016/j.molcel.2015.02.001

    Article  CAS  Google Scholar 

  • Germain D (2016a) Sirtuins and the Estrogen Receptor as Regulators of the Mammalian Mitochondrial UPR in Cancer and Aging. Adv Cancer Res 130:211–56. doi:10.1016/bs.acr.2016.01.004

  • Germain D (2016b) Mitochondrial UPR in Cancer. In: Mitochondria and Cell Death. Springer New York, New York, pp 149–167

  • Gertz J, Savic D, Varley KE et al (2013) Distinct Properties of Cell-Type-Specific and Shared Transcription Factor Binding Sites. Mol Cell 52:25–36. doi:10.1016/j.molcel.2013.08.037

    Article  CAS  Google Scholar 

  • Gitschlag BL, Kirby CS, Samuels DC et al (2016) Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans. Cell Metab 24:91–103. doi:10.1016/j.cmet.2016.06.008

    Article  CAS  Google Scholar 

  • Haigis MC, Deng CX, Finley LWS et al (2012) SIRT3 is a mitochondrial tumor suppressor: A scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 72:2468–2472

    Article  CAS  Google Scholar 

  • Herrmann JM, Riemer J (2010) The intermembrane space of mitochondria. Antioxid Redox Signal 13:1341–1358. doi:10.1089/ars.2009.3063

    Article  CAS  Google Scholar 

  • Imanishi H, Hattori K, Wada R et al (2011) Mitochondrial DNA mutations regulate metastasis of human breast cancer cells. PLoS One. doi:10.1371/journal.pone.0023401

  • Ishikawa K, Hayashi JI (2009) Trading mtDNA uncovers its role in metastasis. Cell Adhes Migr 3:11–13

    Article  Google Scholar 

  • Ishikawa K, Hashizume O, Koshikawa N et al (2008a) Enhanced glycolysis induced by mtDNA mutations does not regulate metastasis. FEBS Lett 582:3525–3530. doi:10.1016/j.febslet.2008.09.024

    Article  CAS  Google Scholar 

  • Ishikawa K, Takenaga K, Akimoto M et al (2008b) ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis. Science (80- ) 320:661–664. doi:10.1126/science.1156906

    Article  CAS  Google Scholar 

  • Jin SM, Youle RJ (2013) The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy. doi:10.4161/auto.26122

  • Kenny TC, Hart P, Ragazzi M et al (2017) Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis. Oncogene. doi:10.1038/onc.2017.52

  • Kim H-S, Patel K, Muldoon-Jacobs K et al (2010) SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17:41–52. doi:10.1016/j.ccr.2009.11.023

    Article  CAS  Google Scholar 

  • Kulawiec M, Owens KM, Singh KK (2009) Cancer cell mitochondria confer apoptosis resistance and promote metastasis. Cancer Biol Ther 8:1378–1385. doi:10.4161/cbt.8.14.8751

    Article  CAS  Google Scholar 

  • Lannigan DA (2003) Estrogen receptor phosphorylation. Steroids 68:1–9

    Article  CAS  Google Scholar 

  • Lemarie A, Grimm S (2011) Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer? Oncogene 30:3985–4003. doi:10.1038/onc.2011.167

    Article  CAS  Google Scholar 

  • Lin Y-F, Schulz AM, Pellegrino MW et al (2016) Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature 533:416–419. doi:10.1038/nature17989

    Article  CAS  Google Scholar 

  • Lombard DB, Tishkoff DX, Bao J (2011) Mitochondrial Sirtuins in the Regulation of Mitochondrial Activity and Metabolic Adaptation. Handb Exp Pharmacol 206:163–88. doi:10.1007/978-3-642-21631-2_8

  • Martinus RD, Garth GP, Webster TL et al (1996) Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur J Biochem 240:98–103. doi:10.1111/j.1432-1033.1996.0098h.x

    Article  CAS  Google Scholar 

  • Mattingly KA, Ivanova MM, Riggs KA et al (2008) Estradiol Stimulates Transcription of Nuclear Respiratory Factor-1 and Increases Mitochondrial Biogenesis. Mol Endocrinol 22:609–622. doi:10.1210/me.2007-0029

    Article  CAS  Google Scholar 

  • McMahon S, LaFramboise T (2014) Mutational patterns in the breast cancer mitochondrial genome, with clinical correlates. Carcinogenesis 35:1046–1054. doi:10.1093/carcin/bgu012

    Article  CAS  Google Scholar 

  • Mohammed H, Russell IA, Stark R et al (2015) Progesterone receptor modulates ERα action in breast cancer. Nature 523:313–317. doi:10.1038/nature14583

    Article  CAS  Google Scholar 

  • Nunes JB, Peixoto J, Soares P et al (2015) OXPHOS dysfunction regulates integrin- 1 modifications and enhances cell motility and migration. Hum Mol Genet 24:1977–1990. doi:10.1093/hmg/ddu612

    Article  CAS  Google Scholar 

  • Papa L, Germain D (2011) Estrogen receptor mediates a distinct mitochondrial unfolded protein response. J Cell Sci 124:1396–1402. doi:10.1242/jcs.078220

    Article  CAS  Google Scholar 

  • Papa L, Germain D (2014) SirT3 regulates the mitochondrial unfolded protein response. Mol Cell Biol 34:699–710. doi:10.1128/MCB.01337-13

    Article  Google Scholar 

  • Papa L, Manfredi G, Germain D (2014) SOD1, an unexpected novel target for cancer therapy. Genes Cancer 5(1-2):15–21

  • Radke S, Chander H, Schäfer P et al (2008) Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi. J Biol Chem 283:12681–12685. doi:10.1074/jbc.C800036200

    Article  CAS  Google Scholar 

  • Ristow M, Schmeisser K (2014) Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose-Response Former Nonlinearity Biol 12:288–341. doi:10.2203/dose-response.13-035.Ristow

    CAS  Google Scholar 

  • Santidrian AF, Matsuno-Yagi A, Ritland M et al (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123:1068–1081. doi:10.1172/JCI64264

    Article  CAS  Google Scholar 

  • Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta, Mol Cell Res 1813:1269–1278

    Article  CAS  Google Scholar 

  • Seo JH, Rivadeneira DB, Caino MC et al (2016) The Mitochondrial Unfoldase-Peptidase Complex ClpXP Controls Bioenergetics Stress and Metastasis. PLoS Biol 14:e1002507. doi:10.1371/journal.pbio.1002507

    Article  Google Scholar 

  • Siegelin MD, Dohi T, Raskett CM et al (2011) Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J Clin Invest 121:1349–1360. doi:10.1172/JCI44855

    Article  Google Scholar 

  • Skrtic M, Sriskanthadevan S, Jhas B et al (2011) Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer Cell 20:674–688. doi:10.1016/j.ccr.2011.10.015

    Article  CAS  Google Scholar 

  • Sun M, Paciga JE, Feldman RI et al (2001) Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res 61:5985–5991. doi:10.1038/nature

    CAS  Google Scholar 

  • Sundaresan NR, Samant SA, Pillai VB et al (2008) SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 28:6384–6401. doi:10.1128/MCB.00426-08

    Article  CAS  Google Scholar 

  • Sundaresan NR, Gupta M, Kim G et al (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119:2758–2771. doi:10.1172/JCI39162

    CAS  Google Scholar 

  • Takibuchi G, Imanishi H, Morimoto M et al (2013) Polymorphic mutations in mouse mitochondrial DNA regulate a tumor phenotype. Mitochondrion 13:881–887. doi:10.1016/j.mito.2013.07.117

    Article  CAS  Google Scholar 

  • Tao R, Coleman MC, Pennington JD et al (2010) Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress. Mol Cell 40:893–904. doi:10.1016/j.molcel.2010.12.013

    Article  CAS  Google Scholar 

  • Tatsuta T, Langer T (2008) Focus Quality Control Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 27(2):306–314. doi:10.1038/sj.emboj.7601972

  • Taylor S, Lam M, Pararasa C et al (2015) Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review. Cancer Cell Int 15:1. doi:10.1186/s12935-015-0156-6

    Article  Google Scholar 

  • Vilgelm A, Lian Z, Wang H et al (2006) Akt-mediated phosphorylation and activation of estrogen receptor alpha is required for endometrial neoplastic transformation in Pten+/− mice. Cancer Res 66:3375–3380. doi:10.1158/0008-5472.CAN-05-4019

    Article  CAS  Google Scholar 

  • Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698. doi:10.1038/nrc3365

    Article  CAS  Google Scholar 

  • Wu C-W, Storey KB (2014) FoxO3a-mediated activation of stress responsive genes during early torpor in a mammalian hibernator. Mol Cell Biochem 390:185–195. doi:10.1007/s11010-014-1969-7

    Article  CAS  Google Scholar 

  • Zhao Q, Wang J, Levichkin IV et al (2002) A mitochondrial specific stress response in mammalian cells. EMBO J 21:4411–4419. doi:10.1093/emboj/cdf445

    Article  CAS  Google Scholar 

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Kenny, T.C., Germain, D. From discovery of the CHOP axis and targeting ClpP to the identification of additional axes of the UPRmt driven by the estrogen receptor and SIRT3. J Bioenerg Biomembr 49, 297–305 (2017). https://doi.org/10.1007/s10863-017-9722-z

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  • DOI: https://doi.org/10.1007/s10863-017-9722-z

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