9. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82: 47–95. 10. Camello-Almaraz C, Gomez-Pinilla PJ, Pozo MJ, Camello PJ (2006) Mitochondrial reactive oxygen species and Ca2+ signaling. Am J Physiol Cell Physiol 291: C1082–1088. 11. Ghafourifar P, Cadenas E (2005) Mitochondrial nitric oxide synthase. Trends Pharmacol Sci 26: 190–195. 12. Hoth M, Button DC, Lewis RS (2000) Mitochondrial control of calcium-channel gating: a mechanism for sustained signaling and transcriptional activation in T lymphocytes. Proc Natl Acad Sci U S A 97: 10607–10612. 13. Hwang I, Shen X, Sprent J (2003) Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: distinct roles for CD54 and B7 molecules. Proc Natl Acad Sci U S A 100: 6670–6675. 14. Kovar M, Boyman O, Shen X, Hwang I, Kohler R, et al. (2006) Direct stimulation of T cells by membrane vesicles from antigen-presenting cells. Proc Natl Acad Sci U S A 103: 11671–11676. 15. Kim K, Wang L, Hwang I (2009) A Novel Flow Cytometric High Throughput Assay for a Systematic Study on Molecular Mechanisms Underlying T Cell Receptor-Mediated Integrin Activation. PLos One 4: e6044. 16. Fang N, Casida JE (1999) Cube resin insecticide: identification and biological activity of 29 rotenoid constituents. J Agric Food Chem 47: 2130–2136. 17. Childs EW, Tharakan B, Hunter FA, Isong M, Liggins ND (2008) Mitochondrial complex III is involved in proapoptotic BAK-induced microvas- cular endothelial cell hyperpermeability. Shock 29: 636–641. 18. Schnermann MJ, Romero FA, Hwang I, Nakamaru-Ogiso E, Yagi T, et al. (2006) Total synthesis of piericidin A1 and B1 and key analogues. J Am Chem Soc 128: 11799–11807. 19. Miyadera H, Shiomi K, Ui H, Yamaguchi Y, Masuma R, et al. (2003) Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase). Proc Natl Acad Sci U S A 100: 473–477. 20. Weber J (2006) ATP synthase: subunit-subunit interactions in the stator stalk. Biochim Biophys Acta 1757: 1162–1170. 21. Thomas R, Kim MH (2007) Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers. Mol Cell Biochem 296: 35–44. 22. Leverve XM, Guigas B, Detaille D, Batandier C, Koceir EA, et al. (2003) Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab 29: 6S88–94. 23. Owen MR, Halestrap AP (1993) The mechanisms by which mild respiratory chain inhibitors inhibit hepatic gluconeogenesis. Biochim Biophys Acta 1142: 11–22. 24. Tamas P, Hawley SA, Clarke RG, Mustard KJ, Green K, et al. (2006) Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 203: 1665–1670. 25. Jin X, Townley R, Shapiro L (2007) Structural Insight into AMPK Regulation: ADP Comes into Play. Structure 15: 1285–1295. 26. Kim K, Wang L, Hwang I (2009) LFA-1-dependent Ca2+ entry following suboptimal T cell receptor triggering proceeds without mobilization of intracellular Ca2+. J Biol Chem 284: 22149–22154. 27. Kanner SB, Grosmaire LS, Ledbetter JA, Damle NK (1993) Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation. Proc Natl Acad Sci U S A 90: 7099–7103. 28. Okkenhaug K, Bilancio A, Emery JL, Vanhaesebroeck B (2004) Phosphoino- sitide 3-kinase in T cell activation and survival. Biochem Soc Trans 32: 332–335. 29. Sykulev Y, Brunmark A, Tsomides TJ, Kageyama S, Jackson M, et al. (1994) High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins. Proc Natl Acad Sci U S A 91: 11487–11491. 30. Acuto O, Cantrell D (2000) T cell activation and the cytoskeleton. Annu Rev Immunol 18: 165–184. 31. Marrack P, Kappler J (2004) Control of T cell viability. Annu Rev Immunol 22: 765–787. 32. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8: 774–785. Mitochondria and TCR Signaling 33. Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J 368: 545–553. 34. Turrens JF, Alexandre A, Lehninger AL (1985) Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237: 408–414. 35. Clements JL, Boerth NJ, Lee JR, Koretzky GA (1999) Integration of T cell receptor-dependent signaling pathways by adapter proteins. Annu Rev Immunol 17: 89–108. 36. Tybulewicz VL (2005) Vav-family proteins in T-cell signalling. Curr Opin Immunol 17: 267–274. 37. Zipfel PA, Bunnell SC, Witherow DS, Gu JJ, Chislock EM, et al. (2006) Role for the Abi/wave protein complex in T cell receptor-mediated proliferation and cytoskeletal remodeling. Curr Biol 16: 35–46. 38. Badour K, Zhang J, Siminovitch KA (2003) The Wiskott-Aldrich syndrome protein: forging the link between actin and cell activation. Immunol Rev 192: 98–112. 39. Dustin ML, Bivona TG, Philips MR (2004) Membranes as messengers in T cell adhesion signaling. Nat Immunol 5: 363–372. 40. Sullivan JE, Brocklehurst KJ, Marley AE, Carey F, Carling D, et al. (1994) Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett 353: 33–36. 41. Guigas B, Taleux N, Foretz M, Detaille D, Andreelli F, et al. (2007) AMP- activated protein kinase-independent inhibition of hepatic mitochondrial oxidative phosphorylation by AICA riboside. Biochem J 404: 499–507. 42. Viollet B, Andreelli F, Jorgensen SB, Perrin C, Flamez D, et al. (2003) Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models. Biochem Soc Trans 31: 216–219. 43. Chun KH, Kosmeder JW 2nd, Sun S, Pezzuto JM, Lotan R, et al. (2003) Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 95: 291–302. 44. Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, et al. (2003) A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. Embo J 22: 4103–4110. 45. Gong Y, Sohn H, Xue L, Firestone GL, Bjeldanes LF (2006) 3,39- Diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1) expression by induction of oxidative stress in human breast cancer cells. Cancer Res 66: 4880–4887. 46. Pereira GC, Branco AF, Matos JA, Pereira SL, Parke D, et al. (2007) Mitochondrially-targeted Effects of Berberine on K1735-M2 Mouse Melanoma Cells Comparison with Direct Effects on Isolated Mitochondrial Fractions. J Pharmacol Exp Ther 323(2): 636–49. 47. Sha WC, Nelson CA, Newberry RD, Kranz DM, Russell JH, et al. (1988) Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice. Nature 335: 271–274. 48. Hwang I, Huang JF, Kishimoto H, Brunmark A, Peterson PA, et al. (2000) T cells can use either T cell receptor or CD28 receptors to absorb and internalize cell surface molecules derived from antigen-presenting cells. J Exp Med 191: 1137–1148. 49. Mahnke DK, Sabina RL (2005) Calcium activates erythrocyte AMP deaminase [isoform E (AMPD3)] through a protein-protein interaction between calmodulin and the N-terminal domain of the AMPD3 polypeptide. Biochemistry 44: 5551–5559. 50. Rabinovitch PS, June CH, Grossmann A, Ledbetter JA (1986) Heterogeneity among T cells in intracellular free calcium responses after mitogen stimulation with PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence with flow cytometry. J Immunol 137: 952–961. 51. Hasbold J, Gett AV, Rush JS, Deenick E, Avery D, et al. (1999) Quantitative analysis of lymphocyte differentiation and proliferation in vitro using carboxy- fluorescein diacetate succinimidyl ester. Immunol Cell Biol 77: 516–522. PLoS ONE | www.plosone.org 11 November 2009 | Volume 4 | Issue 11 | e7738