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Duality of effect of La3+ on mitochondrial permeability transition pore depending on the concentration

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Abstract

In order to explore the role of mitochondria in proliferation promotion and/or apoptosis induction of lanthanum, the mutual influences between La3+ and Ca2+ on mitochondrial permeability transition pore (PTP) opening were investigated with isolated mitochondria from rat liver. The experimental results revealed that La3+ influence the state of mitochondria in a concentration-dependent biphasic manner. La3+ in nanomolar concentrations, acting as a Ca2+ analog, entered mitochondrial matrix via the RuR sensitive Ca2+ channel and elevated ROS level, leading to opening of PTP indicated by mitochondrial swelling, reduction of ΔΨm and cytochrome c release. Inhibition of PTP with 10 μM CsA attenuated the effects of La3+. However, micromolar concentrations La3+ acted mainly as a Ca2+ antagonist, inhibiting PTP opening induced by Ca2+. We postulated that this action of La3+ on mitochondria through interaction with Ca2+ might be involved in the proliferation-promoting and apoptosis induction by La3+.

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Abbreviations

Ln:

Lanthanides

Rh123:

Rhodamine 123

DCFH2-DA:

2′7′-Dichlorofluorescein diacetate

CCCP:

Carbonyl cyanide m-chlorophenylhydrazone

CsA:

Cyclosporin A

RuR:

Ruthenium red

TES:

2-[[Tris (hydroxymethyl) methyl]amino]-1-ethanesulfonicacid

EGTA:

Ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

cyt-c :

Cytochrome c

PTP:

Permeability transition pore

MCU:

Mitochondrial calcium uniporter

Δψm :

Mitochondrial membrane potential

ROS:

Reactive oxygen species

References

  • Anna C, Carmen GR, Montserrat M, Jose C, Fernandez C (2004) Mitochondrial permeability transition induced by reactive oxygen species is independent of cholesterol-regulated membrane fluidity. FEBS Lett 560:63–68. doi:10.1016/S0014-5793(04)00071-7

    Article  Google Scholar 

  • Bakowski D, Glitsch MD, Parekh AB (2001) An examination of the secretion-like coupling model for the activation of the Ca2+ release-activated Ca2+ current I(CRAC) in RBL-1 cells. J Physiol 532:55–71. doi:10.1111/j.1469-7793.2001.0055g.x

    Article  CAS  PubMed  Google Scholar 

  • Beavis AD, Brannan RD, Garlid KD (1985) Swelling and contraction of the mitochondrial matrix. I. A structural interpretation of the relationship between light scattering and matrix volume. J Biol Chem 260:13424–13433

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. doi:10.1016/0003-2697(76)90527-3

    Article  CAS  PubMed  Google Scholar 

  • Broekemeier KM, Dempsey ME, Pfeiffer DR (1989) Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. J Biol Chem 264:7826–7830

    CAS  PubMed  Google Scholar 

  • Carriedo SG, Sensi SL, Yin HZ, Weiss JH (2000) AMPA exposures induce mitochondrial Ca2+ overload and ROS generation in spinal motor neurons in vitro. J Neurosci 20:240–250

    CAS  PubMed  Google Scholar 

  • Emaus RK, Grunwald R, Lemasters JJ (1986) Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: spectral and metabolic properties. Biochim Biophys Acta 850:436–448. doi:10.1016/0005-2728(86)90112-X

    Article  CAS  PubMed  Google Scholar 

  • Gincel D, Zaid H, Shoshan-Barmatz V (2001) Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. Biochem J 358(Pt 1):147–155. doi:10.1042/0264-6021:3580147

    Article  CAS  PubMed  Google Scholar 

  • Greisberg JK, Wolf JM, Wyman J, Zou L, Terek RM (2001) Gadolinium inhibits thymidine incorporation and induces apoptosis in chondrocytes. J Orthop Res 19:797–801. doi:10.1016/S0736-0266(01)00025-0

    Article  CAS  PubMed  Google Scholar 

  • Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15. doi:10.1016/S0014-5793(01)02316-X

    Article  CAS  PubMed  Google Scholar 

  • Ligeret H, Barthelemy S, Bouchard Doulakas G, Carrupt PA, Tillement JP, Labidalle S, Morin D (2004a) Fluoride curcumin derivatives: new mitochondrial uncoupling agents. FEBS Lett 569:37–42. doi:10.1016/j.febslet.2004.05.032

    Article  CAS  PubMed  Google Scholar 

  • Ligeret H, Barthelemy S, Zini R, Tillement JP, Labidalle S, Morin D (2004b) Effects of curcumin and curcumin derivatives on mitochondrial permeability transition pore. Free Radic Biol Med 36:919–929. doi:10.1016/j.freeradbiomed.2003.12.018

    Article  CAS  PubMed  Google Scholar 

  • Lim ML, Lum MG, Hansen TM, Roucou X, Nagley P (2002) On the release of cytochrome c from mitochondria during cell death signaling. J Biomed Sci 9:488–506

    CAS  PubMed  Google Scholar 

  • Liu H, Yuan L, Yang X, Wang K (2003) La3+, Gd3+ and Yb3+ induced changes in mitochondrial structure, membrane permeability, cytochrome c release and intracellular ROS level. Chem Biol Interact 146:27–37. doi:10.1016/S0009-2797(03)00072-3

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Liu H, Yang X, Yang X (2006) Thermodynamic analysis of mitochondria working state. Prog Chem 18:841–848

    CAS  Google Scholar 

  • Luo J, Shi R (2005) Acrolein induces oxidative stress in brain mitochondria. Neurochem Int 46:243–252. doi:10.1016/j.neuint.2004.09.001

    Article  CAS  PubMed  Google Scholar 

  • Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC, Kroemer G (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 187:1261–1271. doi:10.1084/jem.187.8.1261

    Article  CAS  PubMed  Google Scholar 

  • Mcstay GP, Clarke SJ, Halestrap AP (2002) Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J 367:541–548. doi:10.1042/BJ20011672

    Article  CAS  PubMed  Google Scholar 

  • Miller TW, Tormey JM (1993) Calcium displacement by lanthanum in subcellular compartments of rat ventricular myocytes: characterisation by electron probe microanalysis. Cardiovasc Res 27:2106–2112. doi:10.1093/cvr/27.12.2106

    Article  CAS  PubMed  Google Scholar 

  • Morin D, Zini R, Berdeaux A, Tillement JP (2006) Effect of the mitochondrial transition pore inhibitor, S-15176, on rat liver mitochondria: ATP synthase modulation and mitochondrial uncoupling induction. Biochem Pharmacol 72:911–918. doi:10.1016/j.bcp.2006.06.035

    Article  CAS  PubMed  Google Scholar 

  • Nicolli A, Basso E, Petronilli V, Wenger RM, Bernardi P (1996) Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem 271:2185–2192. doi:10.1074/jbc.271.4.2185

    Article  CAS  PubMed  Google Scholar 

  • Petronilli V, Cola C, Bernardi P (1993) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore. II. The minimal requirements for pore induction underscore a key role for transmembrane electrical potential, matrix pH, and matrix Ca2+. J Biol Chem 268:1011–1016

    CAS  PubMed  Google Scholar 

  • Pillai S, Bikle DD (1992) Lanthanum influx into cultured human keratinocytes: effect on calcium flux and terminal differentiation. J Cell Physiol 151:623–629. doi:10.1002/jcp.1041510323

    Article  CAS  PubMed  Google Scholar 

  • Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408. doi:10.1152/physrev.00004.2005

    Article  CAS  PubMed  Google Scholar 

  • Salvi M, Bozac A, Toninello A (2004) Gliotoxin induces Mg2+ efflux from intact brain mitochondria. Neurochem Int 45:759–764. doi:10.1016/j.neuint.2004.01.001

    Article  CAS  PubMed  Google Scholar 

  • Starkov AA, Polster BM, Fiskum G (2002) Regulation of hydrogen peroxide production by brain mitochondria by calcium and Bax. J Neurochem 83(1):220–228. doi:10.1046/j.1471-4159.2002.01153.x

    Article  CAS  PubMed  Google Scholar 

  • Switzer ME (1978) The lanthanide ions as probes of calcium ion binding sites in biological systems. Sci Prog 65:19–30

    CAS  PubMed  Google Scholar 

  • Wang K, Li RC, Cheng Y, Zhu B (1999) Lanthanides—the future drugs? Coord Chem Rev 190–192:297–308. doi:10.1016/S0010-8545(99)00072-7

    Article  Google Scholar 

  • Wu WD, Qin XF, Jing QG, Ji YJ (1994) The inhibitory effects of lanthanides on hydroxyl free radical produced on the surface of chrysotile. J Hyg Toxicol 8:201–202

    Google Scholar 

  • Yu S, Hu J, Yang X, Wang K, Qian ZM (2006) La3+-induced extracellular signal-regulated kinase (ERK) signaling via a metal-sensing mechanism linking proliferation and apoptosis in NIH 3T3 cells. Biochemistry 45:11217–11225. doi:10.1021/bi060895d

    Article  CAS  PubMed  Google Scholar 

  • Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241:139–176

    PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by National Natural Science Foundation of China (No. 20637010 and No. 20671008).

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Authors and Affiliations

  1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, 100083, Beijing, China

    Shuai Dong, Yuebin Zhao, Huixue Liu, Xiaoda Yang & Kui Wang

  2. State Key Laboratory of Natural and Biomimetic Drug, Peking University, 100083, Beijing, China

    Shuai Dong, Yuebin Zhao, Huixue Liu, Xiaoda Yang & Kui Wang

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  1. Shuai Dong
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  2. Yuebin Zhao
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  3. Huixue Liu
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Correspondence to Huixue Liu or Kui Wang.

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Dong, S., Zhao, Y., Liu, H. et al. Duality of effect of La3+ on mitochondrial permeability transition pore depending on the concentration. Biometals 22, 917–926 (2009). https://doi.org/10.1007/s10534-009-9244-1

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