Skip to main content
SpringerLink
Log in

Endoplasmic reticulum stress and calcium imbalance are involved in cadmium-induced lipid aberrancy in Saccharomyces cerevisiae

  • Original Paper
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

The endoplasmic reticulum is the key organelle which controls protein folding, lipid biogenesis, and calcium (Ca2+) homeostasis. Cd exposure in Saccharomyces cerevisiae activated the unfolded protein response and was confirmed by the increased Kar2p expression. Cd exposure in wild-type (WT) cells increased PC levels and the PC biosynthetic genes. Deletion of the two phospholipid methyltransferases CHO2 and OPI3 modulated PC, TAG levels and the lipid droplets with cadmium exposure. Interestingly, we noticed an increase in the calcium levels upon Cd exposure in the mutant cells. This study concluded that Cd interrupted calcium homeostasis-induced lipid dysregulation leading to ER stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Al-Saffar NM, Titley JC, Robertson D, Clarke PA, Jackson LE, Leach MO, Ronen SM (2002) Apoptosis is associated with triacylglycerol accumulationin Jurkat T-cells. Br J Cancer 86:963–970

    Article  CAS  PubMed  Google Scholar 

  • Antebi A, Fink GR (1992) The yeast Ca(2+)-ATPase homologue, PMR1, is required for normal Golgi function and localizes in a novel Golgi-like distribution. Mol Biol Cell 3(6):633–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beyersmann D, Hechtenberg S (1997) Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol 144(2):247–261

    Article  CAS  PubMed  Google Scholar 

  • Biogioli M, Pifferi S, Ragghianti M, Rizzuto R, Pinton P (2008) Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis. Cell Calcium 43:184–195

  • Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911

    Article  CAS  PubMed  Google Scholar 

  • Block-Alper L, Webster P, Zhou X, Supeková L, Wong WH, Schultz PG, Meyer DI (2002) IN02, a positive regulator of lipid biosynthesis, is essential for the formation of inducible membranes in yeast. Mol Biol Cell 1:40–51

    Article  Google Scholar 

  • Bracken C, Beauverger P, Duclos O, Russo RJ, Rogers KA, Husson H, Natoli TA, Ledbetter SR, Janiak P, Ibraghimov-Beskrovnaya O, Bukanov NO (2016) CaMKII as a pathological mediator of ER stress, oxidative stress and mitochondrial dysfunction in a murine model of Nephronophthisis. Am J Phys Renal Phys. doi:10.1152/ajprenal.00426.2015

    Google Scholar 

  • Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89:1341–1378

    Article  CAS  PubMed  Google Scholar 

  • Carman GM, Han GS (2009) Regulation of phospholipid synthesis in yeast. J Lipid Res 50(Suppl):S69–S73

    PubMed  PubMed Central  Google Scholar 

  • Cronin SR, Rao R, Hampton RY (2002) Cod1p/Spf1p is a P-type ATPase involved in ER function and Ca2+ homeostasis. J Cell Biol 157:1017–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen Y, Megyeri M, Chen OC, Condomitti G, Riezman I, Loizides-Mangold U, Abdul-Sada A, Rimon N, Riezman H, Platt FM, Futerman AH, Schuldiner M (2013) The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic reticulum. PLoS One 8(12):e85519

    Article  PubMed  PubMed Central  Google Scholar 

  • Dahlqvist A, Stahl U, Lenman M, Banas A, Lee M, Sandager L, Ronne H, Stymne S (2000) Phospholipid:diacylglycerol acyltransferase: an enzyme that catalyzes the acyl-CoA-independent formation of triacylglycerol in yeast and plants. Proc Natl Acad Sci U S A 97(12):6487–6492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doner G, Edge A (2004) Evaluation of digestion procedures of the determination of iron and zinc in biscuits by flame atomic absorption spectrometry. Anal Chim Acta 520:217–222

    Article  CAS  Google Scholar 

  • Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gardarin A, Chédin S, Lagniel G, Aude JC, Godat E, Catty P, Labarre J (2010) Endoplasmic reticulum is a major target of cadmium toxicity in yeast. Mol Microbiol 76(4):1034–1048

    Article  CAS  PubMed  Google Scholar 

  • Gaynor PM, Gill T, Toutenhoofd S, Summers EF, McGraw P, Homann MJ, Henry SA, Carman GM (1991) Regulation of phosphatidylethanolamine methyltransferase and phospholipid methyltransferase by phospholipid precursors in Saccharomyces cerevisiae. Biochim Biophys Acta 1090(3):326–332

    Article  CAS  PubMed  Google Scholar 

  • Grothe J, Riethmüller J, Tschürtz SM, Raith M, Pynn CJ, Stoll D, Bernhard W (2015) Plasma phosphatidylcholine alterations in cystic fibrosis patients: impaired metabolism and correlation with lung function and inflammation. Cell Physiol Biochem 35(4):1437–1453

    Article  CAS  PubMed  Google Scholar 

  • Ghosh AK, Ramakrishnan G, Rajasekharan R (2008) YLR099C (ICT1) encodes a soluble acyl-CoA-dependent lysophosphatidic acid acyltransferase responsible for enhanced phospholipid synthesis on organic solvent stress in Saccharomyces cerevisiae. J Biol Chem 283(15):9768–9775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Görlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal 8(9–10):1391–1418

    Article  PubMed  Google Scholar 

  • Greenberg ML, Klig LS, Letts VA, Loewy BS, Henry SA (1983) Yeast mutant defective in phosphatidylcholine synthesis. J Bacteriol 153(2):791–799

    CAS  PubMed  PubMed Central  Google Scholar 

  • Groenendyk J, Sreenivasaiah PK, Kim do H, Agellon LB, Michalak M (2010) Biology of endoplasmic reticulum stress in the heart. Circ Res 107(10):1185–1197

    Article  CAS  PubMed  Google Scholar 

  • Hechtenberg S, Beyersmann D (1991) Inhibition of sarcoplasmic reticulum Ca(2+)-ATPase activity by cadmium, lead and mercury. Enzyme 45(3):109–115

    CAS  PubMed  Google Scholar 

  • Hoppins S, Collins SR, Cassidy-Stone A, Hummel E, Devay RM, Lackner LL, Westermann B, Schuldiner M, Weissman JS, Nunnari J (2011) A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. J Cell Biol 195(2):323–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fei W, Wang H, Fu X, Bielby C, Yang H (2009) Conditions of endoplasmic reticulum stress stimulate lipid droplet formation in Saccharomyces cerevisiae. Biochem J 424(1):61–67

    Article  CAS  PubMed  Google Scholar 

  • Farber SA, Slack BE, Blusztajn JK (2000) Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer’s disease. FASEB J 14(14):2198–2206

    Article  CAS  PubMed  Google Scholar 

  • Iorio E, Di Vito M, Spadaro F, Ramoni C, Lococo E, Carnevale R, Lenti L, Strom R, Podo F (2003) Triacsin C inhibits the formation of 1 H NMRvisible mobile lipids and lipid bodies in HuT 78 apoptotic cells. Biochim Biophys Acta 1634:1–14

    Article  CAS  PubMed  Google Scholar 

  • Iwanyshyn WM, Han GS, Carman GM (2004) Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc. J Biol Chem 279(21):21976–21983

    Article  CAS  PubMed  Google Scholar 

  • Jackowski S (1996) Cell cycle regulation of membrane phospholipid metabolism. J Biol Chem 271(34):20219–20222

    Article  CAS  PubMed  Google Scholar 

  • Jacobs RL, Zhao Y, Koonen DP, Sletten T, Su B, Lingrell S, Cao G, Peake DA, Kuo MS, Proctor SD, Kennedy BP, Dyck JR, Vance DE (2010) Impaired de nova choline synthesis explains why phosphatidylethanolamine N-methyltranferase-defiecient mice are protected from diet-induced obesity. J Biol Chem 285(29):22403

  • Jonikas MC, Collins SR, Denic V, Oh E, Quan EM, Schmid V, Weibezahn J, Schwappach B, Walter P, Weissman JS, Schuldiner M (2009) Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science 323(5922):1693–1697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanipes MI, Henry SA (1997) The phospholipid methyltransferases in yeast. Biochim Biophys Acta 1348:134–141

    Article  CAS  PubMed  Google Scholar 

  • Kharroubi I, Ladrière L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL (2004) Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145(11):5087–5096

    Article  CAS  PubMed  Google Scholar 

  • Kimura K, Yamaoka M, Kamisaka Y (2004) Rapid estimation of lipids in oleaginous fungi and yeasts using Nile red fluorescence. J Microbiol Methods 56(3):331–338

    Article  CAS  PubMed  Google Scholar 

  • Kodaki T, Yamashita S (1989) Characterization of the methyltransferases in the yeast phosphatidylethanolamine methylation pathway by selective gene disruption. Eur J Biochem 185(2):243–251

    Article  CAS  PubMed  Google Scholar 

  • Koning AJ, Roberts CJ, Wright RL (1996) Different subcellular localization of Saccharomyces cerevisiae HMG-CoA reductase isozymes at elevated levels corresponds to distinct endoplasmic reticulum membrane proliferations. Mol Biol Cell 5:769–789

    Article  Google Scholar 

  • Lee HS, Nam Y, Chung YH, Kim HR, Park ES, Chung SJ, Kim JH, Sohn UD, Kim HC, Oh KW, Jeong JH (2014) Beneficial effects of phosphatidylcholine on high-fat diet-induced obesity, hyperlipidemia and fatty liver in mice. Life Sci 118(1):7–14

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Malhotra JD, Kaufman RJ (2011) ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb Perspect Biol 3:a004424

    PubMed  PubMed Central  Google Scholar 

  • Mitsuhashi S, Ohkuma A, Talim B, Karahashi M, Koumura T, Aoyama C, Kurihara M, Quinlivan R, Sewry C, Mitsuhashi H, Goto K, Koksal B, Kale G, Ikeda K, Taguchi R, Noguchi S, Hayashi YK, Nonaka I, Sher RB, Sugimoto H, Nakagawa Y, Cox GA, Topaloglu H, Nishino I (2011) A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am J Hum Genet 88:845–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore JP, Johannsson A, Hesketh RT, Smith GA, Metcalfe JC (1984) Calcium signals and phospholipid methylation in eukaryotic cells. Biochem J 221:675–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murata Y, Watanabe T, Sato M, Momose Y, Nakahara T, Oka S, Iwahashi H (2003) Dimethyl sulfoxide exposure facilitates phospholipid biosynthesis and cellular membrane proliferation in yeast cells. J Biol Chem 278(35):33185–33193

    Article  CAS  PubMed  Google Scholar 

  • Muthukumar K, Rajakumar S, Sarkar MN, Nachiappan V (2011) Glutathione peroxidase3 of Saccharomyces cerevisiae protects phospholipids during cadmium-induced oxidative stress. Antonie Van Leeuwenhoek 99:761–771

    Article  CAS  PubMed  Google Scholar 

  • Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461

    Article  PubMed  Google Scholar 

  • Preitschopf W, Lückl H, Summers E, Henry SA, Paltauf F, Kohlwein SD (1993) Molecular cloning of the yeast OPI3 gene as a high copy number suppressor of the cho2 mutation. Curr Genet 23:95–101

    Article  CAS  PubMed  Google Scholar 

  • Prins D, Michalak M (2011) Organellar calcium buffers. Cold Spring Harb Perspect Biol 3(3)

  • Promlek T, Ishiwata-Kimata Y, Shido M, Sakuramoto M, Kohno K, Kimata Y (2011) Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways. Mol Biol Cell 22:3520–3532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajakumar S, Ravi C, Nachiappan V (2016) Defect of zinc transporter ZRT1 ameliorates cadmium induced lipid accumulation in Saccharomyces cerevisiae. Metallomics 8(4):453–460

    Article  CAS  PubMed  Google Scholar 

  • Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    Article  PubMed  Google Scholar 

  • Schuldiner M, Collins SR, Thompson NJ, Denic V, Bhamidipati A, Punna T, Ihmels J, Andrews B, Boone C, Greenblatt JF, Weissman JS, Krogan NJ (2005) Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123(3):507–519

    Article  CAS  PubMed  Google Scholar 

  • Schuler MH, Di Bartolomeo F, Böttinger L, Horvath SE, Wenz LS, Daum G, Becker T (2015) Phosphatidylcholine affects the role of the sorting and assembly machinery in the biogenesis of mitochondrial β-barrel proteinsJ. Biol Chem 290(44):26523–26532

    Article  CAS  Google Scholar 

  • Shadel GS (2005) Mitochondrial DNA, aconitase ‘wraps’ it up. Trends Biochem Sci 30:294–296

    Article  CAS  PubMed  Google Scholar 

  • Sheikhnejad RG, Srivastava PN (1986) Isolation and properties of a phosphatidylcholine-specific phospholipase C from bull seminal plasma. J Biol Chem 261(16):7544–7549

    CAS  PubMed  Google Scholar 

  • Siakotos AN, Rouser G, Fleischer S (1966) Phospholipid composition of human, bovine and frog myelin isolated on a large scale from brain and spinal cord. Lipids 1:85–86

    Article  PubMed  Google Scholar 

  • Sorin A, Rosas G, Rao R (1997) PMR1, a Ca2 + −ATPase in yeast Golgi, has properties distinct from sarco/endoplasmic reticulum and plasma membrane calcium pumps. J Biol Chem 272(15):9895–9901

    Article  CAS  PubMed  Google Scholar 

  • Stone SJ, Vance JE (2000) Phosphatidylserine synthase-1 and −2 are localized to mitochondria-associated membranes. J Biol Chem 275:34534–34540

    Article  CAS  PubMed  Google Scholar 

  • Summers EF, Letts VA, McGraw P, Henry SA (1988) Saccharomyces cerevisiae cho2 mutants are deficient in phospholipid methylation and cross-pathway regulation of inositol synthesis. Genetics 120(4):909–922

    CAS  PubMed  PubMed Central  Google Scholar 

  • Surma MA, Klose C, Peng D, Shales M, Mrejen C, Stefanko A, Braberg H, Gordon DE, Vorkel D, Ejsing CS, Farese R Jr, Simons K, Krogan NJ, Ernst R (2013) A lipid E-MAP identifies Ubx2 as a critical regulator of lipid saturation and lipid bilayer stress. Mol Cell 51(4):519–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452

    Article  PubMed  Google Scholar 

  • Thibault G, Shui G, Kim W, McAlister GC, Ismail N, Gygi SP, Wenk MR, Ng DT (2012) The membrane stress response buffers lethal effects of lipid disequilibrium by reprogramming the protein homeostasis network. Mol Cell 48(1):16–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265:7248–7256

    CAS  PubMed  Google Scholar 

  • Zhang GH, Yamaguchi M, Kimura S, Higham S, Kraus-Friedmann N (1990) Effects of heavy metal on rat liver microsomal Ca2(+)-ATPase and Ca2+ sequestering. Relation to SH groups. J Biol Chem 265(4):2184–2189

    CAS  PubMed  Google Scholar 

  • Zinser E, Sperka-Gottlieb CD, Fasch EV, Kohlwein SD, Paltauf F, Daum G (1991) Phospholipid synthesis and lipid composition of subcellular membranes in the unicellular eukaryote Saccharomyces cerevisiae. J Bacteriol 173(6):2026–2034

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Infrastructure facility by DST-FIST, Biochemistry Department and Confocal microscopy facility by DST-PURSE at Bharathidasan University is gratefully acknowledged. SR is supported by a fellowship from the Rajiv Gandhi National Fellowship Scheme from UGC, INDIA. We thank Prof. Ram Rajasekharan, CSIR-CFTRI, Mysore, INDIA, for providing mutant strains for this work. We also acknowledge Sophisticated Analytical Instruments Facility (SAIF), IIT-M, Chennai, India for helping us to conduct the ICP-OES study.

Author information

Authors and Affiliations

  1. Biomembrane Lab, Department of Biochemistry, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

    Selvaraj Rajakumar, Nagaraj Bhanupriya, Chidambaram Ravi & Vasanthi Nachiappan

Authors
  1. Selvaraj Rajakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nagaraj Bhanupriya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chidambaram Ravi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vasanthi Nachiappan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vasanthi Nachiappan.

Electronic supplementary material

Figure S1

The Kennedy (cki1∆,cpt1∆, and pct1∆) and the methylation pathway (cho2∆, opi3∆) mutant cells were grown up to mid-log phase on YPD medium, harvested and washed twice in sterile water. Fourfold serial dilutions were spotted on to YPD agar plate with 50 μM Cd and incubated at 30 °C for 2 days (DOCX 530 kb)

Table S1

(DOCX 28 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rajakumar, S., Bhanupriya, N., Ravi, C. et al. Endoplasmic reticulum stress and calcium imbalance are involved in cadmium-induced lipid aberrancy in Saccharomyces cerevisiae . Cell Stress and Chaperones 21, 895–906 (2016). https://doi.org/10.1007/s12192-016-0714-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-016-0714-4

Keywords

Search

Navigation