Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation and autoimmunity

Oncotarget

Volumn 6, Issue 25, 2015, Pages 20754-20772

  Uzhachenko, Roman ^a   Shanker, Anil ^a,b   Yarbrough, Wendell G ^c,d   Ivanova, Alla V ^c  

^a MEHARRY MEDICAL COLLEGE   (United States)

^b VANDERBILT INGRAM CANCER CENTER   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d YALE CANCER CENTER   (United States)

Author keywords

Autoimmunity; Calcium; Fus1 Tusc2; Inflammation; Mitochondria; Tumor suppressor

Indexed keywords

CALCIUM ION; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MITOCHONDRIAL PROTEIN; PROTEIN FUS1; TRANSCRIPTION FACTOR NFAT; UNCLASSIFIED DRUG; ADENOSINE TRIPHOSPHATE; CALCIUM; REACTIVE OXYGEN METABOLITE; TUMOR SUPPRESSOR PROTEIN; TUSC2 PROTEIN, HUMAN;

ARTICLE; AUTOIMMUNITY; CALCIUM CELL LEVEL; CALCIUM TRANSPORT; CANCER CELL; CARCINOGENESIS; CELL CYCLE ARREST; CELL SURVIVAL; DOWN REGULATION; FUS1 GENE; GENE EXPRESSION; GENE FUNCTION; GROWTH INHIBITION; HOMEOSTASIS; HUMAN; IMMUNE RESPONSE; IMMUNOREGULATION; IMMUNOSURVEILLANCE; LYMPHOCYTE ACTIVATION; MITOCHONDRIAL RESPIRATION; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; T LYMPHOCYTE; TUMOR GROWTH; TUMOR SUPPRESSOR GENE; ANIMAL; CALCIUM SIGNALING; CELL PROLIFERATION; GLYCOLYSIS; IMMUNOLOGY; INFLAMMATION; METABOLISM; MITOCHONDRION; MUTATION; NEOPLASMS;

ADENOSINE TRIPHOSPHATE; ANIMALS; AUTOIMMUNITY; CALCIUM; CALCIUM SIGNALING; CELL PROLIFERATION; GLYCOLYSIS; HOMEOSTASIS; HUMANS; INFLAMMATION; MITOCHONDRIA; MUTATION; NEOPLASMS; REACTIVE OXYGEN SPECIES; TUMOR SUPPRESSOR PROTEINS;

EID: 84940727398     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.4537     Document Type: Article

References (174)

1. Eisner V, Csordas G, Hajnoczky G. Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle-pivotal roles in Ca(2)(+) and reactive oxygen species signaling. Journal of cell science. 2013; 126:2965-2978.
2. Parekh AB. Mitochondrial regulation of store-operated CRAC channels. Cell calcium. 2008; 44:6-13.
3. Watson R, Parekh AB. Mitochondrial regulation of CRAC channel-driven cellular responses. Cell calcium. 2012; 52:52-56.
4. Maciolek JA, Pasternak JA, Wilson HL. Metabolism of activated T lymphocytes. Current opinion in immunology. 2014; 27:60-74.
5. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013; 342:1242454.
6. Wang R, Green DR. Metabolic reprogramming and metabolic dependency in T cells. Immunological reviews. 2012; 249:14-26.
7. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107:8788-8793.
8. Gill T, Levine AD. Mitochondria-derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction. The Journal of biological chemistry. 2013; 288:26246-26255.
9. Kaminski MM, Roth D, Sass S, Sauer SW, Krammer PH, Gulow K. Manganese superoxide dismutase: a regulator of T cell activation-induced oxidative signaling and cell death. Biochimica et biophysica acta. 2012; 1823:1041-1052.
10. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, Bryce PJ, Chandel NS. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013; 38:225-236.
11. Weinberg SE, Sena LA, Chandel NS. Mitochondria in the Regulation of Innate and Adaptive Immunity. Immunity. 2015; 42:406-417.
12. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 140:883-899.
13. Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer research. 2000; 60:6116-6133.
14. Prudkin L, Behrens C, Liu DD, Zhou X, Ozburn NC, Bekele BN, Minna JD, Moran C, Roth JA, Ji L, Wistuba II. Loss and reduction of FUS1 protein expression is a frequent phenomenon in the pathogenesis of lung cancer. Clin Cancer Res. 2008; 14:41-47.
15. Ivanov SV, Miller J, Lucito R, Tang C, Ivanova AV, Pei J, Carbone M, Cruz C, Beck A, Webb C, Nonaka D, Testa JR, Pass HI. Genomic events associated with progression of pleural malignant mesothelioma. Int J Cancer. 2009; 124:589-599.
16. Li G, Kawashima H, Ji L, Ogose A, Ariizumi T, Umezu H, Xu Y, Hotta T, Endo N. Frequent absence of tumor suppressor FUS1 protein expression in human bone and soft tissue sarcomas. Anticancer research. 31:11-21.
17. Demokan S, Chuang AY, Chang X, Khan T, Smith IM, Pattani KM, Dasgupta S, Begum S, Khan Z, Liegeois NJ, Westra WH, Sidransky D, Koch W, Califano JA. Identification of guanine nucleotide-binding protein gamma-7 as an epigenetically silenced gene in head and neck cancer by gene expression profiling. International journal of oncology. 2013; 42:1427-1436.
18. Kondo M, Ji L, Kamibayashi C, Tomizawa Y, Randle D, Sekido Y, Yokota J, Kashuba V, Zabarovsky E, Kuzmin I, Lerman M, Roth J, Minna JD. Overexpression of candidate tumor suppressor gene FUS1 isolated from the 3p21.3 homozygous deletion region leads to G1 arrest and growth inhibition of lung cancer cells. Oncogene. 2001; 20:6258-6262.
19. Uno F, Sasaki J, Nishizaki M, Carboni G, Xu K, Atkinson EN, Kondo M, Minna JD, Roth JA, Ji L. Myristoylation of the fus1 protein is required for tumor suppression in human lung cancer cells. Cancer research. 2004; 64:2969-2976.
20. Ito I, Ji L, Tanaka F, Saito Y, Gopalan B, Branch CD, Xu K, Atkinson EN, Bekele BN, Stephens LC, Minna JD, Roth JA, Ramesh R. Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo. Cancer Gene Ther. 2004; 11:733-739.
21. Lin J, Sun T, Ji L, Deng W, Roth J, Minna J, Arlinghaus R. Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1. Oncogene. 2007; 26:6989-6996.
22. Deng WG, Kawashima H, Wu G, Jayachandran G, Xu K, Minna JD, Roth JA, Ji L. Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells. Cancer research. 2007; 67:709-717.
23. Deng WG, Wu G, Ueda K, Xu K, Roth JA, Ji L. Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1. Cancer Gene Ther. 2008; 15:29-39.
24. Du L, Schageman JJ, Subauste MC, Saber B, Hammond SM, Prudkin L, Wistuba II, Ji L, Roth JA, Minna JD, Pertsemlidis A. miR-93, miR-98, and miR-19 regulate expression of tumor suppressor gene FUS1. Mol Cancer Res. 2009; 7:1234-1243.
25. Lin J, Xu K, Gitanjali J, Roth JA, Ji L. Regulation of tumor suppressor gene FUS1 expression by the untranslated regions of mRNA in human lung cancer cells. Biochemical and biophysical research communications. 2011; 410:235-241.
26. Rutnam ZJ, Du WW, Yang W, Yang X, Yang BB. The pseudogene TUSC2P promotes TUSC2 function by binding multiple microRNAs. Nature communications. 2014; 5:2914.
27. Ji L, Roth JA. Tumor suppressor FUS1 signaling pathway. J Thorac Oncol. 2008; 3:327-330.
28. Lu C, Stewart DJ, Lee JJ, Ji L, Ramesh R, Jayachandran G, Nunez MI, Wistuba II, Erasmus JJ, Hicks ME, Grimm EA, Reuben JM, Baladandayuthapani V, Templeton NS, McMannis JD, Roth JA. Phase I clinical trial of systemically administered TUSC2(FUS1)-nanoparticles mediating functional gene transfer in humans. PloS one. 2012; 7:e34833.
29. Ren J, Yu C, Wu S, Peng F, Jiang Q, Zhang X, Zhong G, Shi H, Chen X, Su X, Luo X, Zhu W, Wei Y. Cationic liposome mediated delivery of FUS1 and hIL-12 coexpression plasmid demonstrates enhanced activity against human lung cancer. Current cancer drug targets. 2014; 14:167-180.
30. Li L, Yu C, Ren J, Ye S, Ou W, Wang Y, Yang W, Zhong G, Chen X, Shi H, Su X, Chen L, Zhu W. Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo. Journal of cancer research and clinical oncology. 2014; 140:895-907.
31. Meng J, Majidi M, Fang B, Ji L, Bekele BN, Minna JD, Roth JA. The tumor suppressor gene TUSC2 (FUS1) sensitizes NSCLC to the AKT inhibitor MK2206 in LKB1-dependent manner. PloS one. 2013; 8:e77067.
32. Kuraishy A, Karin M, Grivennikov SI. Tumor promotion via injury-and death-induced inflammation. Immunity. 2011; 35:467-477.
33. Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nature reviews Cancer. 2013; 13:759-771.
34. Uzhachenko R, Issaeva N, Boyd K, Ivanov SV, Carbone DP, Ivanova AV. Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis. J Pathol. 2012; 227:456-469.
35. Ivanova AV, Ivanov SV, Prudkin L, Nonaka D, Liu Z, Tsao A, Wistuba I, Roth J, Pass HI. Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects. Molecular cancer. 2009; 8:91.
36. Ivanova AV, Ivanov SV, Pascal V, Lumsden JM, Ward JM, Morris N, Tessarolo L, Anderson SK, Lerman MI. Autoimmunity, spontaneous tumourigenesis, and IL-15 insufficiency in mice with a targeted disruption of the tumour suppressor gene Fus1. J Pathol. 2007; 211:591-601.
37. Hesson LB, Cooper WN, Latif F. Evaluation of the 3p21.3 tumour-suppressor gene cluster. Oncogene. 2007; 26:7283-7301.
38. Lin J, Arlinghaus R. Activated c-Abl tyrosine kinase in malignant solid tumors. Oncogene. 2008; 27:4385-4391.
39. Jayachandran G, Roth JA, Ji L. Analysis of protein-protein interaction using proteinchip array-based SELDI-TOF mass spectrometry. Methods in molecular biology. 2012; 818:217-226.
40. Uzhachenko R, Ivanov SV, Yarbrough WG, Shanker A, Medzhitov R, Ivanova AV. Fus1/Tusc2 is a novel regulator of mitochondrial calcium handling, Ca2+-coupled mitochondrial processes, and Ca2+-dependent NFAT and NF-kappaB pathways in CD4+ T cells. Antioxidants & redox signaling. 2014; 20:1533-1547.
41. Zozulya S, Stryer L. Calcium-myristoyl protein switch. Proceedings of the National Academy of Sciences of the United States of America. 1992; 89:11569-11573.
42. Hood MI, Uzhachenko R, Boyd K, Skaar EP, Ivanova AV. Loss of mitochondrial protein Fus1 augments host resistance to Acinetobacter baumannii infection. Infection and immunity. 2013; 81:4461-4469.
43. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004; 287:C817-833.
44. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011; 476:341-345.
45. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011; 476:336-340.
46. Csordas G, Golenar T, Seifert EL, Kamer KJ, Sancak Y, Perocchi F, Moffat C, Weaver D, de la Fuente Perez S, Bogorad R, Koteliansky V, Adijanto J, Mootha VK, Hajnoczky G. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca(2)(+) uniporter. Cell metabolism. 2013; 17:976-987.
47. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK. MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature. 2010; 467:291-296.
48. Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot J, Speciner L, Taneja N, Oshea J, Koteliansky V, Mootha VK. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PloS one. 2013; 8:e55785.
49. Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Muller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, et al. MCUR1 is an essential component of mitochondrial Ca(2+) uptake that regulates cellular metabolism. Nature cell biology. 2012; 14:1336-1343.
50. Pendin D, Greotti E, Pozzan T. The elusive importance of being a mitochondrial Ca(2+) uniporter. Cell calcium. 2014; 55:139-145.
51. Beutner G, Sharma VK, Lin L, Ryu SY, Dirksen RT, Sheu SS. Type 1 ryanodine receptor in cardiac mitochondria: transducer of excitation-metabolism coupling. Biochimica et biophysica acta. 2005; 1717:1-10.
52. Trenker M, Malli R, Fertschai I, Levak-Frank S, Graier WF. Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nature cell biology. 2007; 9:445-452.
53. Jiang D, Zhao L, Clapham DE. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science. 2009; 326:144-147.
54. Palty R, Hershfinkel M, Sekler I. Molecular identity and functional properties of the mitochondrial Na+/Ca2+ exchanger. The Journal of biological chemistry. 2012; 287:31650-31657.
55. Palty R, Sekler I. The mitochondrial Na(+)/Ca(2+) exchanger. Cell calcium. 2012; 52:9-15.
56. Glancy B, Balaban RS. Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry. 2012; 51:2959-2973.
57. Brookes PS. Mitochondrial H(+) leak and ROS generation: an odd couple. Free radical biology & medicine. 2005; 38:12-23.
58. Marchi S, Giorgi C, Suski JM, Agnoletto C, Bononi A, Bonora M, De Marchi E, Missiroli S, Patergnani S, Poletti F, Rimessi A, Duszynski J, Wieckowski MR, Pinton P. Mitochondria-ros crosstalk in the control of cell death and aging. Journal of signal transduction. 2012; 2012:329635.
59. Murphy MP. How mitochondria produce reactive oxygen species. The Biochemical journal. 2009; 417:1-13.
60. Aon MA, Cortassa S, Maack C, O'Rourke B. Sequential opening of mitochondrial ion channels as a function of glutathione redox thiol status. The Journal of biological chemistry. 2007; 282:21889-21900.
61. Ben-Hail D, Palty R, Shoshan-Barmatz V. Measurement of mitochondrial Ca2+ transport mediated by three transport proteins: VDAC1, the Na+/Ca2+ exchanger, and the Ca2+ uniporter. Cold Spring Harbor protocols. 2014; 2014:161-166.
62. Kaddour-Djebbar I, Choudhary V, Brooks C, Ghazaly T, Lakshmikanthan V, Dong Z, Kumar MV. Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells. International journal of oncology. 2010; 36:1437-1444.
63. Takeuchi A, Kim B, Matsuoka S. The destiny of Ca(2+) released by mitochondria. The journal of physiological sciences: JPS. 2015; 65:11-24.
64. De Marchi U, Santo-Domingo J, Castelbou C, Sekler I, Wiederkehr A, Demaurex N. NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. The Journal of biological chemistry. 2014; 289:20377-20385.
65. Liu T, O'Rourke B. Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circulation research. 2008; 103:279-288.
66. Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, O'Rourke B. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circulation research. 2006; 99:172-182.
67. Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Bohm M, O'Rourke B, Maack C. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation. 2010; 121:1606-1613.
68. Liu T, O'Rourke B. Regulation of mitochondrial Ca2+ and its effects on energetics and redox balance in normal and failing heart. Journal of bioenergetics and biomembranes. 2009; 41:127-132.
69. Halestrap AP. What is the mitochondrial permeability transition pore? Journal of molecular and cellular cardiology. 2009; 46:821-831.
70. Guha M, Avadhani NG. Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion. 2013; 13:577-591.
71. Kasahara A, Scorrano L. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends in cell biology. 2014; 24:761-770.
72. Bergmeier W, Weidinger C, Zee I, Feske S. Emerging roles of store-operated Ca(2)(+) entry through STIM and ORAI proteins in immunity, hemostasis and cancer. Channels. 2013; 7:379-391.
73. Shaw PJ, Qu B, Hoth M, Feske S. Molecular regulation of CRAC channels and their role in lymphocyte function. Cellular and molecular life sciences: CMLS. 2013; 70:2637-2656.
74. Feissner RF, Skalska J, Gaum WE, Sheu SS. Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci. Landmark Ed2009; 14:1197-1218.
75. Deak AT, Blass S, Khan MJ, Groschner LN, Waldeck-Weiermair M, Hallstrom S, Graier WF, Malli R. IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. Journal of cell science. 2014; 127:2944-2955.
76. Samanta K, Bakowski D, Parekh AB. Key role for store-operated Ca2+ channels in activating gene expression in human airway bronchial epithelial cells. PloS one. 2014; 9:e105586.
77. Ishii K, Hirose K, Iino M. Ca2+ shuttling between endoplasmic reticulum and mitochondria underlying Ca2+ oscillations. EMBO reports. 2006; 7:390-396.
78. Hernandez-SanMiguel E, Vay L, Santo-Domingo J, Lobaton CD, Moreno A, Montero M, Alvarez J. The mitochondrial Na+/Ca2+ exchanger plays a key role in the control of cytosolic Ca2+ oscillations. Cell calcium. 2006; 40:53-61.
79. Takeuchi A, Kim B, Matsuoka S. The mitochondrial Na+-Ca2+ exchanger, NCLX, regulates automaticity of HL-1 cardiomyocytes. Scientific reports. 2013; 3:2766.
80. Kim MS, Usachev YM. Mitochondrial Ca2+ cycling facilitates activation of the transcription factor NFAT in sensory neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2009; 29:12101-12114.
81. Parnis J, Montana V, Delgado-Martinez I, Matyash V, Parpura V, Kettenmann H, Sekler I, Nolte C. Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2013; 33:7206-7219.
82. Kim B, Takeuchi A, Koga O, Hikida M, Matsuoka S. Pivotal role of mitochondrial Na(+)(-)Ca(2)(+) exchange in antigen receptor mediated Ca(2)(+) signalling in DT40 and A20 B lymphocytes. The Journal of physiology. 2012; 590:459-474.
83. Dupont G, Combettes L, Bird GS, Putney JW. Calcium oscillations. Cold Spring Harbor perspectives in biology. 2011; 3.
84. Smedler E, Uhlen P. Frequency decoding of calcium oscillations. Biochimica et biophysica acta. 2014; 1840:964-969.
85. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature. 1997; 386:855-858.
86. Dolmetsch RE, Xu K, Lewis RS. Calcium oscillations increase the efficiency and specificity of gene expression. Nature. 1998; 392:933-936.
87. Lewis RS. Calcium oscillations in T-cells: mechanisms and consequences for gene expression. Biochemical Society transactions. 2003; 31:925-929.
88. Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Frontiers in oncology. 2013; 3:292.
89. De Koninck P, Schulman H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science. 1998; 279:227-230.
90. Parekh AB. Decoding cytosolic Ca2+ oscillations. Trends in biochemical sciences. 2011; 36:78-87.
91. Samanta K, Douglas S, Parekh AB. Mitochondrial calcium uniporter MCU supports cytoplasmic Ca2+ oscillations, store-operated Ca2+ entry and Ca2+-dependent gene expression in response to receptor stimulation. PloS one. 2014; 9:e101188.
92. Marcu R, Wiczer BM, Neeley CK, Hawkins BJ. Mitochondrial matrix Ca(2)(+) accumulation regulates cytosolic NAD(+)/NADH metabolism, protein acetylation, and sirtuin expression. Molecular and cellular biology. 2014; 34:2890-2902.
93. Cortassa S, Aon MA, Marban E, Winslow RL, O'Rourke B. An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J. 2003; 84:2734-2755.
94. Tanaka T, Ames JB, Harvey TS, Stryer L, Ikura M. Sequestration of the membrane-targeting myristoyl group of recoverin in the calcium-free state. Nature. 1995; 376:444-447.
95. Ames JB, Ishima R, Tanaka T, Gordon JI, Stryer L, Ikura M. Molecular mechanics of calcium-myristoyl switches. Nature. 1997; 389:198-202.
96. Li CC, Wu TS, Huang CF, Jang LT, Liu YT, You ST, Liou GG, Lee FJ. GTP-binding-defective ARL4D alters mitochondrial morphology and membrane potential. PloS one. 2012; 7:e43552.
97. Darshi M, Trinh KN, Murphy AN, Taylor SS. Targeting and import mechanism of coiled-coil helix coiled-coil helix domain-containing protein 3 (ChChd3) into the mitochondrial intermembrane space. The Journal of biological chemistry. 2012; 287:39480-39491.
98. Borgese N, Aggujaro D, Carrera P, Pietrini G, Bassetti M. A role for N-myristoylation in protein targeting: NADH-cytochrome b5 reductase requires myristic acid for association with outer mitochondrial but not ER membranes. The Journal of cell biology. 1996; 135:1501-1513.
99. Colombo S, Longhi R, Alcaro S, Ortuso F, Sprocati T, Flora A, Borgese N. N-myristoylation determines dual targeting of mammalian NADH-cytochrome b5 reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning. The Journal of cell biology. 2005; 168:735-745.
100. Utsumi T, Sakurai N, Nakano K, Ishisaka R. C-terminal 15 kDa fragment of cytoskeletal actin is posttranslationally N-myristoylated upon caspase-mediated cleavage and targeted to mitochondria. FEBS letters. 2003; 539:37-44.
101. Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science. 2000; 290:1761-1765.
102. Hajnoczky G, Booth D, Csordas G, Debattisti V, Golenar T, Naghdi S, Niknejad N, Paillard M, Seifert EL, Weaver D. Reliance of ER-mitochondrial calcium signaling on mitochondrial EF-hand Ca2+ binding proteins: Miros, MICUs, LETM1 and solute carriers. Current opinion in cell biology. 2014; 29:133-141.
103. de la Fuente S, Matesanz-Isabel J, Fonteriz RI, Montero M, Alvarez J. Dynamics of mitochondrial Ca2+ uptake in MICU1-knockdown cells. The Biochemical journal. 2014; 458:33-40.
104. Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell. 2012; 151:630-644.
105. Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Molecular cell. 2014; 53:726-737.
106. Doonan PJ, Chandramoorthy HC, Hoffman NE, Zhang X, Cardenas C, Shanmughapriya S, Rajan S, Vallem S, Chen X, Foskett JK, Cheung JY, Houser SR, Madesh M. LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2014.
107. Feldman B, Fedida-Metula S, Nita J, Sekler I, Fishman D. Coupling of mitochondria to store-operated Ca(2+)-signaling sustains constitutive activation of protein kinase B/Akt and augments survival of malignant melanoma cells. Cell calcium. 2010; 47:525-537.
108. Bauer G. Targeting extracellular ROS signaling of tumor cells. Anticancer research. 2014; 34:1467-1482.
109. Bonner MY, Arbiser JL. Targeting NADPH oxidases for the treatment of cancer and inflammation. Cellular and molecular life sciences: CMLS. 2012; 69:2435-2442.
110. Dikalov SI, Li W, Doughan AK, Blanco RR, Zafari AM. Mitochondrial reactive oxygen species and calcium uptake regulate activation of phagocytic NADPH oxidase. American journal of physiology Regulatory, integrative and comparative physiology. 2012; 302:R1134-1142.
111. Marchi S, Pinton P. Mitochondrial calcium uniporter, MiRNA and cancer: Live and let die. Communicative & integrative biology. 2013; 6:e23818.
112. Demaria M, Giorgi C, Lebiedzinska M, Esposito G, D'Angeli L, Bartoli A, Gough DJ, Turkson J, Levy DE, Watson CJ, Wieckowski MR, Provero P, Pinton P, Poli V. A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging. 2010; 2:823-842.
113. Marchi S, Lupini L, Patergnani S, Rimessi A, Missiroli S, Bonora M, Bononi A, Corra F, Giorgi C, De Marchi E, Poletti F, Gafa R, Lanza G, Negrini M, Rizzuto R, Pinton P. Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Current biology: CB. 2013; 23:58-63.
114. Arvizo RR, Moyano DF, Saha S, Thompson MA, Bhattacharya R, Rotello VM, Prakash YS, Mukherjee P. Probing novel roles of the mitochondrial uniporter in ovarian cancer cells using nanoparticles. The Journal of biological chemistry. 2013; 288:17610-17618.
115. Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J, Schwarz EC, Hoth M. T cell activation requires mitochondrial translocation to the immunological synapse. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104:14418-14423.
116. Baixauli F, Martin-Cofreces NB, Morlino G, Carrasco YR, Calabia-Linares C, Veiga E, Serrador JM, Sanchez-Madrid F. The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse. The EMBO journal. 30:1238-1250.
117. Wang X, Schwarz TL. The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. Cell. 2009; 136:163-174.
118. Junker C, Hoth M. Immune synapses: mitochondrial morphology matters. The EMBO journal. 30: 1187-1189.
119. Ledderose C, Bao Y, Lidicky M, Zipperle J, Li L, Strasser K, Shapiro NI, Junger WG. Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling. The Journal of biological chemistry. 2014; 289:25936-25945.
120. Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 109 Suppl. 2002; 109:S67-79.
121. Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harbor perspectives in biology. 2009; 1:a000034.
122. Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Molecular cancer. 2013; 12:86.
123. Bourgeais J, Gouilleux-Gruart V, Gouilleux F. Oxidative metabolism in cancer: A STAT affair? Jak-Stat. 2013; 2:e25764.
124. Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harbor perspectives in biology. 2009; 1:a000141.
125. Qin JJ, Nag S, Wang W, Zhou J, Zhang WD, Wang H, Zhang R. NFAT as cancer target: mission possible? Biochimica et biophysica acta. 2014; 1846:297-311.
126. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature reviews Cancer. 2014; 14:736-746.
127. Akl H, Bultynck G. Altered Ca(2+) signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors. Biochimica et biophysica acta. 2013; 1835:180-193.
128. Tischner D, Woess C, Ottina E, Villunger A. Bcl-2-regulated cell death signalling in the prevention of autoimmunity. Cell death & disease. 2010; 1:e48.
129. Murphy AN, Bredesen DE, Cortopassi G, Wang E, Fiskum G. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proceedings of the National Academy of Sciences of the United States of America. 1996; 93:9893-9898.
130. Hanson CJ, Bootman MD, Distelhorst CW, Maraldi T, Roderick HL. The cellular concentration of Bcl-2 determines its pro-or anti-apoptotic effect. Cell calcium. 2008; 44:243-258.
131. Hanson CJ, Bootman MD, Distelhorst CW, Wojcikiewicz RJ, Roderick HL. Bcl-2 suppresses Ca2+ release through inositol 1, 5-trisphosphate receptors and inhibits Ca2+ uptake by mitochondria without affecting ER calcium store content. Cell calcium. 2008; 44:324-338.
132. Minagawa N, Kruglov EA, Dranoff JA, Robert ME, Gores GJ, Nathanson MH. The anti-apoptotic protein Mcl-1 inhibits mitochondrial Ca2+ signals. The Journal of biological chemistry. 2005; 280:33637-33644.
133. Xiao K, Wang Y, Chang Z, Lao Y, Chang DC. p32, a novel binding partner of Mcl-1, positively regulates mitochondrial Ca(2+) uptake and apoptosis. Biochemical and biophysical research communications. 2014; 451:322-328.
134. Pierson W, Cauwe B, Policheni A, Schlenner SM, Franckaert D, Berges J, Humblet-Baron S, Schonefeldt S, Herold MJ, Hildeman D, Strasser A, Bouillet P, Lu LF, Matthys P, Freitas AA, Luther RJ, et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3(+) regulatory T cells. Nature immunology. 2013; 14:959-965.
135. Haque R, Lei F, Xiong X, Wu Y, Song J. FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development. Arthritis research & therapy. 2010; 12:R66.
136. Koenen P, Heinzel S, Carrington EM, Happo L, Alexander WS, Zhang JG, Herold MJ, Scott CL, Lew AM, Strasser A, Hodgkin PD. Mutually exclusive regulation of T cell survival by IL-7R and antigen receptor-induced signals. Nature communications. 2013; 4:1735.
137. Panneerselvam P, Singh LP, Selvarajan V, Chng WJ, Ng SB, Tan NS, Ho B, Chen J, Ding JL. T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell death and differentiation. 2013; 20:478-489.
138. Huang H, Hu X, Eno CO, Zhao G, Li C, White C. An interaction between Bcl-xL and the voltage-dependent anion channel (VDAC) promotes mitochondrial Ca2+ uptake. The Journal of biological chemistry. 2013; 288:19870-19881.
139. Ludwinski MW, Sun J, Hilliard B, Gong S, Xue F, Carmody RJ, DeVirgiliis J, Chen YH. Critical roles of Bim in T cell activation and T cell-mediated autoimmune inflammation in mice. The Journal of clinical investigation. 2009; 119:1706-1713.
140. Campbell HG, Slatter TL, Jeffs A, Mehta R, Rubio C, Baird M, Braithwaite AW. Does Delta133p53 isoform trigger inflammation and autoimmunity? Cell cycle. 2012; 11:446-450.
141. Kawashima H, Takatori H, Suzuki K, Iwata A, Yokota M, Suto A, Minamino T, Hirose K, Nakajima H. Tumor suppressor p53 inhibits systemic autoimmune diseases by inducing regulatory T cells. Journal of immunology. 2013; 191:3614-3623.
142. Zheng SJ, Lamhamedi-Cherradi SE, Wang P, Xu L, Chen YH. Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function. Diabetes. 2005; 54:1423-1428.
143. Madan E, Gogna R, Keppler B, Pati U. p53 increases intra-cellular calcium release by transcriptional regulation of calcium channel TRPC6 in GaQ3-treated cancer cells. PloS one. 2013; 8:e71016.
144. Sorrentino G, Mioni M, Giorgi C, Ruggeri N, Pinton P, Moll U, Mantovani F, Del Sal G. The prolyl-isomerase Pin1 activates the mitochondrial death program of p53. Cell death and differentiation. 2013; 20:198-208.
145. Tsokos GC. Calcium signaling in systemic lupus erythematosus lymphocytes and its therapeutic exploitation. Arthritis and rheumatism. 2008; 58:1216-1219.
146. Feske S. Calcium signalling in lymphocyte activation and disease. Nature reviews Immunology. 2007; 7:690-702.
147. Izquierdo JH, Bonilla-Abadia F, Canas CA, Tobon GJ. Calcium, channels, intracellular signaling and autoimmunity. Reumatologia clinica. 2014; 10:43-47.
148. Zhang W, Zhou Q, Xu W, Cai Y, Yin Z, Gao X, Xiong S. DNA-dependent activator of interferon-regulatory factors (DAI) promotes lupus nephritis by activating the calcium pathway. The Journal of biological chemistry. 2013; 288:13534-13550.
149. Perl A, Fernandez DR, Telarico T, Doherty E, Francis L, Phillips PE. T-cell and B-cell signaling biomarkers and treatment targets in lupus. Curr Opin Rheumatol. 2009; 21:454-464.
150. Schwarz A, Tutsch E, Ludwig B, Schwarz EC, Stallmach A, Hoth M. Ca2+ signaling in identified T-lymphocytes from human intestinal mucosa. Relation to hyporeactivity, proliferation, and inflammatory bowel disease. The Journal of biological chemistry. 2004; 279:5641-5647.
151. Cope AP. Studies of T-cell activation in chronic inflammation. Arthritis research. 2002; 4:S197-211.
152. McCarl CA, Khalil S, Ma J, Oh-hora M, Yamashita M, Roether J, Kawasaki T, Jairaman A, Sasaki Y, Prakriya M, Feske S. Store-operated Ca2+ entry through ORAI1 is critical for T cell-mediated autoimmunity and allograft rejection. Journal of immunology. 2010; 185:5845-5858.
153. Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunological reviews. 2014; 259:88-102.
154. Hillhouse EE, Lesage S. A comprehensive review of the phenotype and function of antigen-specific immunoregulatory double negative T cells. Journal of autoimmunity. 2013; 40:58-65.
155. Crispin JC, Tsokos GC. Human TCR-alpha beta+ CD4-CD8-T cells can derive from CD8+ T cells and display an inflammatory effector phenotype. Journal of immunology. 2009; 183:4675-4681.
156. Fernandez DR, Telarico T, Bonilla E, Li Q, Banerjee S, Middleton FA, Phillips PE, Crow MK, Oess S, Muller-Esterl W, Perl A. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. Journal of immunology. 2009; 182:2063-2073.
157. Fernandez D, Perl A. mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discovery medicine. 2010; 9:173-178.
158. Wing LY, Chen HM, Chuang PC, Wu MH, Tsai SJ. The mammalian target of rapamycin-p70 ribosomal S6 kinase but not phosphatidylinositol 3-kinase-Akt signaling is responsible for fibroblast growth factor-9-induced cell proliferation. The Journal of biological chemistry. 2005; 280:19937-19947.
159. Ito N, Ruegg UT, Kudo A, Miyagoe-Suzuki Y, Takeda S. Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy. Nature medicine. 2013; 19:101-106.
160. Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nature reviews Immunology. 2012; 12:325-338.
161. Kwon G, Marshall CA, Pappan KL, Remedi MS, McDaniel ML. Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. Diabetes. 2004; 53:S225-232.
162. Dardalhon V, Korn T, Kuchroo VK, Anderson AC. Role of Th1 and Th17 cells in organ-specific autoimmunity. Journal of autoimmunity. 2008; 31:252-256.
163. Fanger CM, Neben AL, Cahalan MD. Differential Ca2+ influx, KCa channel activity, and Ca2+ clearance distinguish Th1 and Th2 lymphocytes. Journal of immunology. 2000; 164:1153-1160.
164. Frossi B, De Carli M, Piemonte M, Pucillo C. Oxidative microenvironment exerts an opposite regulatory effect on cytokine production by Th1 and Th2 cells. Molecular immunology. 2008; 45:58-64.
165. Murakami N, Riella LV. Co-inhibitory pathways and their importance in immune regulation. Transplantation. 2014; 98:3-14.
166. Pasero C, Olive D. Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity. Immunology letters. 2013; 151:71-75.
167. Austin JW, Lu P, Majumder P, Ahmed R, Boss JM. STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. Journal of immunology. 2014; 192:4876-4886.
168. Yao S, Wang S, Zhu Y, Luo L, Zhu G, Flies S, Xu H, Ruff W, Broadwater M, Choi IH, Tamada K, Chen L. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood. 2009; 113:5811-5818.
169. Carrithers LM, Hulseberg P, Sandor M, Carrithers MD. The human macrophage sodium channel NaV1.5 regulates mycobacteria processing through organelle polarization and localized calcium oscillations. FEMS immunology and medical microbiology. 2011; 63:319-327.
170. Segal BH, Grimm MJ, Khan AN, Han W, Blackwell TS. Regulation of innate immunity by NADPH oxidase. Free radical biology & medicine. 2012; 53:72-80.
171. Nunes P, Demaurex N, Dinauer MC. Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis. Traffic. 2013; 14:1118-1131.
172. Sun B, Wang X, Ji Z, Wang M, Liao YP, Chang CH, Li R, Zhang H, Nel AE, Xia T. NADPH Oxidase-Dependent NLRP3 Inflammasome Activation and its Important Role in Lung Fibrosis by Multiwalled Carbon Nanotubes. Small. 2015.
173. Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P. Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochimica et biophysica acta. 2009; 1787:1342-1351.
174. Csordas G, Hajnoczky G. SR/ER-mitochondrial local communication: calcium and ROS. Biochimica et biophysica acta. 2009; 1787:1352-1362.