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

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+.

[1]  M. Dempsey,et al.  Cyclosporin A is a potent inhibitor of the inner membrane permeability transition in liver mitochondria. , 1989, The Journal of biological chemistry.

[2]  R. Shi,et al.  Acrolein induces oxidative stress in brain mitochondria , 2005, Neurochemistry International.

[3]  J. Wolf,et al.  Gadolinium inhibits thymidine incorporation and induces apoptosis in chondrocytes , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[4]  S. Sensi,et al.  AMPA Exposures Induce Mitochondrial Ca2+ Overload and ROS Generation in Spinal Motor Neurons In Vitro , 2000, The Journal of Neuroscience.

[5]  A. Beavis,et al.  Swelling and contraction of the mitochondrial matrix. I. A structural interpretation of the relationship between light scattering and matrix volume. , 1985, The Journal of biological chemistry.

[6]  P. Bernardi,et al.  Interactions of Cyclophilin with the Mitochondrial Inner Membrane and Regulation of the Permeability Transition Pore, a Cyclosporin A-sensitive Channel (*) , 1996, The Journal of Biological Chemistry.

[7]  Kui Wang,et al.  Lanthanides—the future drugs? , 1999 .

[8]  V. Shoshan-Barmatz,et al.  Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. , 2001, The Biochemical journal.

[9]  Gary Fiskum,et al.  Regulation of hydrogen peroxide production by brain mitochondria by calcium and Bax , 2002, Journal of neurochemistry.

[10]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[11]  J. Tillement,et al.  Effect of the mitochondrial transition pore inhibitor, S-15176, on rat liver mitochondria: ATP synthase modulation and mitochondrial uncoupling induction. , 2006, Biochemical pharmacology.

[12]  Z. Qian,et al.  La(3+)-induced extracellular signal-regulated kinase (ERK) signaling via a metal-sensing mechanism linking proliferation and apoptosis in NIH 3T3 cells. , 2006, Biochemistry.

[13]  A. Parekh,et al.  An examination of the secretion‐like coupling model for the activation of the Ca2+ release‐activated Ca2+ current ICRAC in RBL‐1 cells , 2001, The Journal of physiology.

[14]  G. Kroemer,et al.  The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins , 1998, The Journal of experimental medicine.

[15]  J. Lemasters,et al.  Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: spectral and metabolic properties. , 1986, Biochimica et biophysica acta.

[16]  M. Zoratti,et al.  The mitochondrial permeability transition. , 1995, Biochimica et biophysica acta.

[17]  P. Carrupt,et al.  Fluoride curcumin derivatives: new mitochondrial uncoupling agents , 2004, FEBS letters.

[18]  J. M. Tormey,et al.  Calcium displacement by lanthanum in subcellular compartments of rat ventricular myocytes: characterisation by electron probe microanalysis. , 1993, Cardiovascular research.

[19]  X. Roucou,et al.  On the release of cytochrome c from mitochondria during cell death signaling. , 2002, Journal of biomedical science.

[20]  M. Salvi,et al.  Gliotoxin induces Mg2+ efflux from intact brain mitochondria , 2004, Neurochemistry International.

[21]  Z. Qian,et al.  La3+-Induced Extracellular Signal-Regulated Kinase (ERK) Signaling via a Metal-Sensing Mechanism Linking Proliferation and Apoptosis in NIH 3T3 Cells† , 2006 .

[22]  Kui Wang,et al.  La(3+), Gd(3+) and Yb(3+) induced changes in mitochondrial structure, membrane permeability, cytochrome c release and intracellular ROS level. , 2003, Chemico-biological interactions.

[23]  Tullio Pozzan,et al.  Microdomains of intracellular Ca2+: molecular determinants and functional consequences. , 2006, Physiological reviews.

[24]  A. Colell,et al.  Mitochondrial permeability transition induced by reactive oxygen species is independent of cholesterol‐regulated membrane fluidity , 2004, FEBS letters.

[25]  D. Bikle,et al.  Lanthanum influx into cultured human keratinocytes: Effect on calcium flux and terminal differentiation , 1992, Journal of cellular physiology.

[26]  A E Vercesi,et al.  Mitochondrial permeability transition and oxidative stress , 2001, FEBS letters.

[27]  A. Halestrap,et al.  Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. , 2002, The Biochemical journal.

[28]  J. Tillement,et al.  Effects of curcumin and curcumin derivatives on mitochondrial permeability transition pore. , 2004, Free radical biology & medicine.

[29]  P. Bernardi,et al.  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+. , 1993, The Journal of biological chemistry.