鈣離子是細胞訊號傳導中常見的第二信使，在細胞生存中扮演關鍵角色。鈣訊號傳導影響各種細胞行為，例如增殖、遷移和凋亡，最終導致疾病的發生。初級纖毛可作為細胞膜上的細胞感測器，檢測細胞外訊號並調節細胞反應。自噬作用是一把雙面刃，控制著細胞的生存。然而，鈣離子、初級纖毛和自噬之間的相互作用強調了它們之間複雜的關係，因此在本研究中要來單獨探討鈣離子與初級纖毛和細胞自噬的關聯。為了驗證鈣離子與初級纖毛以及自噬作用之間的關係，我們採用化學和光遺傳學方法來操縱細胞內鈣濃度。我們發現，使用thapsigargin 活化鈣池操縱的鈣內流或鈣離子載體離子黴素增加細胞內鈣離子濃度導致纖毛解體和增強自噬作用。相反，鈣螯合劑 BAPTA-AM 降低細胞內鈣水平，促進纖毛生成並抑制自噬作用。光遺傳學調控光敏感通道CatCh創造不同鈣離子震盪，顯示高頻鈣振盪誘導纖毛分解並增加自噬作用。 此外，鈣離子透過活化 Aurora A 抑制纖毛生長，鈣離子並透過 AMPK 活化促進自噬作用增加，導致細胞死亡。雖然先前的研究已經探討了初級纖毛和自噬之間的關係，但我們的研究結果表明，鈣離子可以獨立調節初級纖毛和自噬，這與先前初級纖毛和自噬之間的關聯不同。

Calcium ions (Ca2+) serve as common secondary messengers in cellular signaling, playing pivotal roles in cell survival. Ca2+ influences various cellular behaviors such as proliferation, migration, and apoptosis, ultimately contributing to the onset of diseases. Primary cilia, acting as cellular sensors on the cell membrane, detect extracellular signals and modulate cellular responses. Autophagy, a double-edged sword, governs cell survival. However, the interplay among Ca2+, primary cilia, and autophagy underscores their intricate relationship, prompting the need to individually investigate their associations in this study. To validate the relationship between Ca2+ and primary cilia as well as autophagy, we employed chemical and optogenetic approaches to manipulate intracellular Ca2+ concentrations. We found that activation of store-operated calcium entry (SOCE) by thapsigargin or Ca2+ ionophore ionomycin increased intracellular Ca2+ levels, leading to ciliary disassembly and enhanced autophagy. Conversely, Ca2+ chelator BAPTA-AM reduced intracellular Ca2+ levels, promoting ciliogenesis and inhibiting autophagy. Optogenetic manipulation using the light-sensitive channel CatCh generated distinct Ca2+ oscillations, revealing that high-frequency Ca2+ oscillations induced ciliary disassembly and increased autophagy. Furthermore, Ca2+ inhibited ciliogenesis by activating Aurora A and Ca2+ promoted increased autophagy leading to cell death through AMPK activation. While previous studies have explored the relationship between primary cilia and autophagy, our findings demonstrate that Ca2+ can independently regulate primary cilia and autophagy, diverging from previous associations between primary cilia and autophagy.

1. Takahashi A, Camacho P, Lechleiter JD & Herman B (1999) Measurement of intracellular calcium. Physiological Reviews, 79(4), 1089–1125. https://doi.org/10.1152/physrev.1999.79.4.1089
2. Clapham DE (2007) Calcium signaling. Cell, 131(6), 1047–1058. https://doi.org/10.1016/j.cell.2007.11.028
3. Bootman MD (2012) Calcium signaling. Cold Spring Harbor Perspectives in Biology, 4(7), a011171. https://doi.org/10.1101/cshperspect.a011171
4. Swann K & Parrington J (1999) Mechanism of Ca2+ release at fertilization in mammals. The Journal of Experimental Zoology, 285(3), 267–275. https://doi.org/10.1002/(sici)1097-010x(19991015)285:3<267::aid-jez10>3.0.co;2-p
5. Wakai T, Vanderheyden V & Fissore RA (2011) Ca2+ signaling during mammalian fertilization: requirements, players, and adaptations. Cold Spring Harbor Perspectives in Biology, 3(4), a006767. https://doi.org/10.1101/cshperspect.a006767
6. Szent-Györgyi AG (1975) Calcium regulation of muscle contraction. Biophysical Journal, 15(7), 707–723. https://doi.org/10.1016/S0006-3495(75)85849-8
7. Südhof TC (2012) Calcium control of neurotransmitter release. Cold Spring Harbor Perspectives in Biology, 4(1), a011353. https://doi.org/10.1101/cshperspect.a011353
8. Petersen OH & Verkhratsky A (2016) Calcium and ATP control multiple vital functions. Philosophical Transactions of the Royal Society B, 371(1700), 20150418. https://doi.org/10.1098/rstb.2015.0418
9. Gail MH, Boone CW & Thompson CS (1973) A calcium requirement for fibroblast motility and prolifertion. Experimental Cell Research, 79(2), 386–390. https://doi.org/10.1016/0014-4827(73)90458-8
10. Zhivotovsky B & Orrenius S (2011) Calcium and cell death mechanisms: a perspective from the cell death community. Cell Calcium, 50(3), 211–221. https://doi.org/10.1016/j.ceca.2011.03.003
11. Stewart TA, Yapa KT & Monteith GR (2015) Altered calcium signaling in cancer cells. Biochimica et Biophysica Acta, 1848(10 Pt B), 2502–2511. https://doi.org/10.1016/j.bbamem.2014.08.016
12. Azimi I & Monteith GR (2016) Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells. Endocrine-Related Cancer, 23(11), R517–R525. https://doi.org/10.1530/ERC-16-0334
13. Li T, Chen J & Zeng Z (2021) Pathophysiological role of calcium channels and transporters in the multiple myeloma. Cell Communication and Signaling, 19(1), 99. https://doi.org/10.1186/s12964-021-00781-4
14. Moonga BS, Li S, Iqbal J, Davidson R, Shankar VS, Bevis PJ, Inzerillo A, Abe E, Huang CL & Zaidi M (2002) Ca2+ influx through the osteoclastic plasma membrane ryanodine receptor. American Journal of Physiology-Renal Physiology, 282(5), F921–F932. https://doi.org/10.1152/ajprenal.00045.2000
15. Lu L (2021) Mobilizing ER IP3 receptors as a mechanism to enhance calcium signaling. Cellular & Molecular Immunology, 18(9), 2284–2285. https://doi.org/10.1038/s41423-021-00725-5
16. Chen YF, Chen YT, Chiu WT & Shen MR (2013) Remodeling of calcium signaling in tumor progression. Journal of Biomedical Science, 20(1), 23. https://doi.org/10.1186/1423-0127-20-23
17. Hogan PG & Rao A (2015) Store-operated calcium entry: mechanisms and modulation. Biochemical and Biophysical Research Communications, 460(1), 40–49. https://doi.org/10.1016/j.bbrc.2015.02.110
18. Prakriya M & Lewis RS (2015) Store-operated calcium channels. Physiological Reviews, 95(4), 1383–1436. https://doi.org/10.1152/physrev.00020.2014
19. Palk L, Sneyd J, Patterson K, Shuttleworth TJ, Yule DI, Maclaren O & Crampin EJ (2012) Modelling the effects of calcium waves and oscillations on saliva secretion. Journal of Theoretical Biology, 305, 45–53. https://doi.org/10.1016/j.jtbi.2012.04.009
20. Samanta K & Parekh AB (2017) Spatial Ca2+ profiling: decrypting the universal cytosolic Ca2+ oscillation. The Journal of Physiology, 595(10), 3053–3062. https://doi.org/10.1113/JP272860
21. Bohineust A, Garcia Z, Corre B, Lemaître F & Bousso P (2020) Optogenetic manipulation of calcium signals in single T cells in vivo. Nature Communications, 11(1), 1143. https://doi.org/10.1038/s41467-020-14810-2
22. Berridge MJ, Bootman MD & Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nature Reviews, 4(7), 517–529. https://doi.org/10.1038/nrm1155
23. Whitaker M (2006) Calcium at fertilization and in early development. Physiological Reviews, 86(1), 25–88. https://doi.org/10.1152/physrev.00023.2005
24. Sun S, Liu Y, Lipsky S & Cho M (2007) Physical manipulation of calcium oscillations facilitates osteodifferentiation of human mesenchymal stem cells. FASEB Journal, 21(7), 1472–1480. https://doi.org/10.1096/fj.06-7153com
25. Lai YS, Chang YH, Chen YY, Xu J, Yu CS, Chang SJ, Chen PS, Tsai SJ & Chiu WT (2021) Ca2+ -regulated cell migration revealed by optogenetically engineered Ca2+ oscillations. Journal of Cellular Physiology, 236(6), 4681–4693. https://doi.org/10.1002/jcp.30190
26. Lai YS, Chang CC, Chen YY, Nguyen TMH, Xu J, Chen YC, Chang YF, Wang CY, Chen PS, Lin SC, Peng IC, Tsai SJ & Chiu WT (2023) Optogenetically engineered Ca2+ oscillation-mediated DRP1 activation promotes mitochondrial fission and cell death. Journal of Cell Science, 136(12), jcs260819. https://doi.org/10.1242/jcs.260819
27. Dewenter M, von der Lieth A, Katus HA & Backs J (2017) Calcium signaling and transcriptional regulation in cardiomyocytes. Circulation Research, 121(8), 1000–1020. https://doi.org/10.1161/CIRCRESAHA.117.310355
28. Thiel G, Schmidt T & Rössler OG (2021) Ca2+ microdomains, calcineurin and the regulation of gene transcription. Cells, 10(4), 875. https://doi.org/10.3390/cells10040875
29. Tsai FC, Kuo GH, Chang SW & Tsai PJ (2015) Ca2+ signaling in cytoskeletal reorganization, cell migration, and cancer metastasis. BioMed Research International, 2015, 409245. https://doi.org/10.1155/2015/409245
30. Paupe V & Prudent J (2018) New insights into the role of mitochondrial calcium homeostasis in cell migration. Biochemical and Biophysical Research Communications, 500(1), 75–86. https://doi.org/10.1016/j.bbrc.2017.05.039
31. Görlach A, Bertram K, Hudecova S & Krizanova O (2015) Calcium and ROS: A mutual interplay. Redox Biology, 6, 260–271. https://doi.org/10.1016/j.redox.2015.08.010
32. Pathak T & Trebak M (2018) Mitochondrial Ca2+ signaling. Pharmacology & Therapeutics, 192, 112–123. https://doi.org/10.1016/j.pharmthera.2018.07.001
33. Patra S, Mahapatra KK, Praharaj PP, Panigrahi DP, Bhol CS, Mishra SR, Behera BP, Singh A, Jena M & Bhutia SK (2021) Intricate role of mitochondrial calcium signalling in mitochondrial quality control for regulation of cancer cell fate. Mitochondrion, 57, 230–240. https://doi.org/10.1016/j.mito.2021.01.002
34. Kahl CR & Means AR (2003) Regulation of cell cycle progression by calcium/calmodulin-dependent pathways. Endocrine Reviews, 24(6), 719–736. https://doi.org/10.1210/er.2003-0008
35. Machaca K (2010) Ca2+ signaling, genes and the cell cycle. Cell Calcium, 48(5), 243–250. https://doi.org/10.1016/j.ceca.2010.10.003
36. Orrenius S, Zhivotovsky B & Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nature Reviews, 4(7), 552–565. https://doi.org/10.1038/nrm1150
37. Harr MW & Distelhorst CW (2010) Apoptosis and autophagy: decoding calcium signals that mediate life or death. Cold Spring Harbor Perspectives in Biology, 2(10), a005579. https://doi.org/10.1101/cshperspect.a005579
38. Seeley ES & Nachury MV (2010) The perennial organelle: assembly and disassembly of the primary cilium. Journal of Cell Science, 123(4), 511–518. https://doi.org/10.1242/jcs.061093
39. Bernabé-Rubio M & Alonso MA (2017) Routes and machinery of primary cilium biogenesis. Cellular and Molecular Life Sciences, 74(22), 4077–4095. https://doi.org/10.1007/s00018-017-2570-5
40. Ainsworth C (2007) Cilia: tails of the unexpected. Nature, 448(7154), 638–641. https://doi.org/10.1038/448638a
41. Liang Y, Meng D, Zhu B & Pan J (2016) Mechanism of ciliary disassembly. Cellular and Molecular Life Sciences, 73(9), 1787–1802. https://doi.org/10.1007/s00018-016-2148-7
42. Satir P, Pedersen LB & Christensen ST (2010) The primary cilium at a glance. Journal of Cell Science, 123(4), 499–503. https://doi.org/10.1242/jcs.050377
43. Higgins M, Obaidi I & McMorrow T (2019) Primary cilia and their role in cancer. Oncology Letters, 17(3), 3041–3047. https://doi.org/10.3892/ol.2019.9942
44. Girardet L, Augière C, Asselin MP & Belleannée C (2019) Primary cilia: biosensors of the male reproductive tract. Andrology, 7(5), 588–602. https://doi.org/10.1111/andr.12650
45. Hassounah NB, Bunch TA & McDermott KM (2012) Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling. Clinical Cancer Research, 18(9), 2429–2435. https://doi.org/10.1158/1078-0432.CCR-11-0755
46. Bangs F & Anderson KV (2017) Primary cilia and mammalian hedgehog signaling. Cold Spring Harbor Perspectives in Biology, 9(5), a028175. https://doi.org/10.1101/cshperspect.a028175
47. Anvarian Z, Mykytyn K, Mukhopadhyay S, Pedersen LB & Christensen ST (2019) Cellular signalling by primary cilia in development, organ function and disease. Nature Reviews Nephrology, 15(4), 199–219. https://doi.org/10.1038/s41581-019-0116-9
48. Brennan D, Chen X, Cheng L, Mahoney M & Riobo NA (2012) Noncanonical Hedgehog signaling. Vitamins and Hormones, 88, 55–72. https://doi.org/10.1016/B978-0-12-394622-5.00003-1
49. Teperino R, Aberger F, Esterbauer H, Riobo N & Pospisilik JA (2014) Canonical and non-canonical Hedgehog signalling and the control of metabolism. Seminars in Cell & Developmental Biology, 33, 81–92. https://doi.org/10.1016/j.semcdb.2014.05.007
50. Hamilton AM, Balashova OA & Borodinsky LN (2021) Non-canonical Hedgehog signaling regulates spinal cord and muscle regeneration in Xenopus laevis larvae. eLife, 10, e61804. https://doi.org/10.7554/eLife.61804
51. Abou Alaiwi WA, Lo ST & Nauli SM (2009) Primary cilia: highly sophisticated biological sensors. Sensors, 9(9), 7003–7020. https://doi.org/10.3390/s90907003
52. Masyuk AI, Gradilone SA & LaRusso NF (2014) Calcium signaling in cilia and ciliary-mediated intracellular calcium signaling: are they independent or coordinated molecular events? Hepatology, 60(5), 1783–1785. https://doi.org/10.1002/hep.27331
53. Pala R, Alomari N & Nauli SM (2017) Primary cilium-dependent signaling mechanisms. International Journal of Molecular Sciences, 18(11), 2272. https://doi.org/10.3390/ijms18112272
54. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE & Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genetics, 33(2), 129–137. https://doi.org/10.1038/ng1076
55. Gradilone SA, Masyuk AI, Splinter PL, Banales JM, Huang BQ, Tietz PS, Masyuk TV & Larusso NF (2007) Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proceedings of the National Academy of Sciences, 104(48), 19138–19143. https://doi.org/10.1073/pnas.0705964104
56. Alenmyr L, Uller L, Greiff L, Högestätt ED & Zygmunt PM (2014) TRPV4-mediated calcium influx and ciliary activity in human native airway epithelial cells. Basic and Clinical Pharmacology and Toxicology, 114(2), 210–216. https://doi.org/10.1111/bcpt.12135
57. Liu X, Vien T, Duan J, Sheu SH, DeCaen PG & Clapham DE (2018) Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. eLife, 7, e33183. https://doi.org/10.7554/eLife.33183
58. DeCaen PG, Delling M, Vien TN & Clapham DE (2013) Direct recording and molecular identification of the calcium channel of primary cilia. Nature, 504(7479), 315–318. https://doi.org/10.1038/nature12832
59. Izawa I, Goto H, Kasahara K & Inagaki M (2015) Current topics of functional links between primary cilia and cell cycle. Cilia, 4, 12. https://doi.org/10.1186/s13630-015-0021-1
60. Kuhns S, Schmidt KN, Reymann J, Gilbert DF, Neuner A, Hub B, Carvalho R, Wiedemann P, Zentgraf H, Erfle H, Klingmüller U, Boutros M & Pereira G (2013) The microtubule affinity regulating kinase MARK4 promotes axoneme extension during early ciliogenesis. The Journal of Cell Biology, 200(4), 505–522. https://doi.org/10.1083/jcb.201206013
61. Sami N, Kumar V, Hassan MI (2016) Microtubule affinity regulating kinase-4. Encyclopedia of Signaling Molecules. 1–16. https://doi.org/10.1007/978-1-4614-6438-9_101744-1
62. Dai G, Qian Y, Chen J, Meng FL, Pan FY, Shen WG, Zhang SZ, Xue B & Li CJ (2013) Calmodulin activation of polo-like kinase 1 is required during mitotic entry. Biochemistry and Cell Biology, 91(5), 287–294. https://doi.org/10.1139/bcb-2013-0015
63. Wang G, Chen Q, Zhang X, Zhang B, Zhuo X, Liu J, Jiang Q & Zhang C (2013) PCM1 recruits Plk1 to the pericentriolar matrix to promote primary cilia disassembly before mitotic entry. Journal of Cell Science, 126(Pt 6), 1355–1365. https://doi.org/10.1242/jcs.114918
64. Plotnikova OV, Pugacheva EN, Dunbrack RL & Golemis EA (2010) Rapid calcium-dependent activation of Aurora-A kinase. Nature Communications, 1(6), 64. https://doi.org/10.1038/ncomms1061
65. Shagisultanova E, Dunbrack RL, Jr & Golemis EA (2015) Issues in interpreting the in vivo activity of Aurora-A. Expert Opinion on Therapeutic Targets, 19(2), 187–200. https://doi.org/10.1517/14728222.2014.981154
66. Goto H, Inoko A & Inagaki M (2013) Cell cycle progression by the repression of primary cilia formation in proliferating cells. Cellular and Molecular Life Sciences, 70(20), 3893–3905. https://doi.org/10.1007/s00018-013-1302-8
67. Goto H, Inaba H & Inagaki M (2017) Mechanisms of ciliogenesis suppression in dividing cells. Cellular and Molecular Life Sciences, 74(5), 881–890. https://doi.org/10.1007/s00018-016-2369-9
68. Youn YH & Han YG (2018) Primary cilia in brain development and diseases. The American Journal of Pathology, 188(1), 11–22. https://doi.org/10.1016/j.ajpath.2017.08.031
69. Mill P, Christensen ST & Pedersen LB (2023) Primary cilia as dynamic and diverse signalling hubs in development and disease. Nature Reviews, 24(7), 421–441. https://doi.org/10.1038/s41576-023-00587-9
70. Yoder BK (2007) Role of primary cilia in the pathogenesis of polycystic kidney disease. Journal of the American Society of Nephrology, 18(5), 1381–1388. https://doi.org/10.1681/ASN.2006111215
71. Huang L & Lipschutz JH (2014) Cilia and polycystic kidney disease, kith and kin. Birth Defects Research. Part C: Embryo Today, 102(2), 174–185. https://doi.org/10.1002/bdrc.21066
72. Ma M (2021) Cilia and polycystic kidney disease. Seminars in Cell & Developmental Biology, 110, 139–148. https://doi.org/10.1016/j.semcdb.2020.05.003
73. Burnight ER, Wiley LA, Drack AV, Braun TA, Anfinson KR, Kaalberg EE, Halder JA, Affatigato LM, Mullins RF, Stone EM & Tucker BA (2014) CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype. Gene Therapy, 21(7), 662–672. https://doi.org/10.1038/gt.2014.39
74. Sun C, Zhou J & Meng X (2021) Primary cilia in retinal pigment epithelium development and diseases. Journal of Cellular and Molecular Medicine, 25(19), 9084–9088. https://doi.org/10.1111/jcmm.16882
75. Li X, Guo S, Su Y, Lu J, Hang D, Cao S, Fu Q & Li Z (2022) Role of primary cilia in skeletal disorders. Stem Cells International, 2022, 6063423. https://doi.org/10.1155/2022/6063423
76. Tian X, Zhao H & Zhou J (2023) Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond. eLife, 12, e87623. https://doi.org/10.7554/eLife.87623
77. Jenks AD, Vyse S, Wong JP, Kostaras E, Keller D, Burgoyne T, Shoemark A, Tsalikis A, de la Roche M, Michaelis M, Cinatl J, Jr Huang PH & Tanos BE (2018) Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer. Cell Reports, 23(10), 3042–3055. https://doi.org/10.1016/j.celrep.2018.05.016
78. Lauth M, Bergström A, Shimokawa T, Tostar U, Jin Q, Fendrich V, Guerra C, Barbacid M & Toftgård R (2010) DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nature Structural & Molecular Biology, 17(6), 718–725. https://doi.org/10.1038/nsmb.1833
79. Christensen ST, Morthorst SK, Mogensen JB & Pedersen LB (2017) Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor β (TGF-β) Signaling. Cold Spring Harbor Perspectives in Biology, 9(6), a028167. https://doi.org/10.1101/cshperspect.a028167
80. Shao J, Xu L, Chen L, Lu Q, Xie X, Shi W, Xiong H, Shi C, Huang X, Mei J, Rao H, Lu H, Lu N & Luo S (2017) Arl13b promotes gastric tumorigenesis by regulating Smo trafficking and activation of the hedgehog signaling pathway. Cancer Research, 77(15), 4000–4013. https://doi.org/10.1158/0008-5472.CAN-16-2461
81. Shireman JM, Atashi F, Lee G, Ali ES, Saathoff MR, Park CH, Savchuk S, Baisiwala S, Miska J, Lesniak MS, James CD, Stupp R, Kumthekar P, Horbinski CM, Ben-Sahra I & Ahmed AU (2021) De novo purine biosynthesis is a major driver of chemoresistance in glioblastoma. Brain, 144(4), 1230–1246. https://doi.org/10.1093/brain/awab020
82. Campoy E & Colombo MI (2009) Autophagy in intracellular bacterial infection. Biochimica et Biophysica Acta, 1793(9), 1465–1477. https://doi.org/10.1016/j.bbamcr.2009.03.003
83. Choi Y, Bowman JW & Jung JU (2018) Autophagy during viral infection – a double-edged sword. Nature Reviews Microbiology, 16(6), 341–354. https://doi.org/10.1038/s41579-018-0003-6
84. Lahiri V, Hawkins WD & Klionsky DJ (2019) Watch what you (self-) eat: autophagic mechanisms that modulate metabolism. Cell Metabolism, 29(4), 803–826. https://doi.org/10.1016/j.cmet.2019.03.003
85. Gross AS & Graef M (2020) Mechanisms of autophagy in metabolic stress response. Journal of Molecular Biology, 432(1), 28–52. https://doi.org/10.1016/j.jmb.2019.09.005
86. Kitada M & Koya D (2021) Autophagy in metabolic disease and ageing. Nature Reviews Endocrinology, 17(11), 647–661. https://doi.org/10.1038/s41574-021-00551-9
87. Codogno P & Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death and Differentiation, 12(2), 1509–1518. https://doi.org/10.1038/sj.cdd.4401751
88. Zhang J (2013) Autophagy and mitophagy in cellular damage control. Redox Biology, 1(1), 19–23. https://doi.org/10.1016/j.redox.2012.11.008
89. Filomeni G, De Zio D & Cecconi F (2015) Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death and Differentiation, 22(3), 377–388. https://doi.org/10.1038/cdd.2014.150
90. Mizushima N & Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell, 147(4), 728–741. https://doi.org/10.1016/j.cell.2011.10.026
91. Feng Y, He D, Yao Z & Klionsky DJ (2014) The machinery of macroautophagy. Cell Research, 24(1), 24–41. https://doi.org/10.1038/cr.2013.168
92. Parzych KR & Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxidants and Redox Signaling, 20(3), 460–473. https://doi.org/10.1089/ars.2013.5371
93. Kim YC & Guan KL (2015) mTOR: a pharmacologic target for autophagy regulation. The Journal of Clinical Investigation, 125(1), 25–32. https://doi.org/10.1172/JCI73939
94. Li Y & Chen Y (2019) AMPK and autophagy. Advances in Experimental Medicine and Biology, 1206, 85–108. https://doi.org/10.1007/978-981-15-0602-4_4
95. Mizushima N (2007) Autophagy: process and function. Genes and Development, 21(22), 2861–2873. https://doi.org/10.1101/gad.1599207
96. Glick D, Barth S & Macleod KF (2010) Autophagy: cellular and molecular mechanisms. The Journal of Pathology, 221(1), 3–12. https://doi.org/10.1002/path.2697
97. Hansen M, Rubinsztein DC & Walker DW (2018) Autophagy as a promoter of longevity: insights from model organisms. Nature Reviews Molecular Cell Biology, 19(9), 579–593. https://doi.org/10.1038/s41580-018-0033-y
98. Decuypere JP, Bultynck G & Parys JB (2011) A dual role for Ca2+ in autophagy regulation. Cell Calcium, 50(3), 242–250. https://doi.org/10.1016/j.ceca.2011.04.001
99. Kim J, Kundu M, Violle B & Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology, 13(2), 132–141. https://doi.org/10.1038/ncb2152
100. Alers S, Löffler AS, Wesselborg S & Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Molecular and Cellular Biology, 32(1), 2–11. https://doi.org/10.1128/MCB.06159-11
101. Lin Y, Hupp TR & Stevens C (2010) Death-associated protein kinase (DAPK) and signal transduction: additional roles beyond cell death. The FEBS Journal, 277(1), 48–57. https://doi.org/10.1111/j.1742-4658.2009.07411.x
102. Filippi-Chiela EC, Viegas MS, Thomé MP, Buffon A, Wink MR & Lenz G (2016) Modulation of autophagy by calcium signalosome in human disease. Molecular Pharmacology, 90(3), 371–384. https://doi.org/10.1124/mol.116.105171
103. Bootman MD, Chehab T, Bultynck G, Parys JB & Rietdorf K (2018) The regulation of autophagy by calcium signals: do we have a consensus? Cell Calcium, 70, 32–46. https://doi.org/10.1016/j.ceca.2017.08.005
104. Hippert MM, O'Toole PS & Thorburn A (2006) Autophagy in cancer: good, bad, or both? Cancer Research, 66(19), 9349–9351. https://doi.org/10.1158/0008-5472.CAN-06-1597
105. Singh SS, Vats S, Chia AY, Tan TZ, Deng S, Ong MS, Arfuso F, Yap CT, Goh BC, Sethi G, Huang RY, Shen HM, Manjithaya R & Kumar AP (2018) Dual role of autophagy in hallmarks of cancer. Oncogene, 37(9), 1142–1158. https://doi.org/10.1038/s41388-017-0046-6
106. Chen C, Gao H & Su X (2021) Autophagy-related signaling pathways are involved in cancer (Review). Experimental and Therapeutic Medicine, 22(1), 710. https://doi.org/10.3892/etm.2021.10142
107. Debnath J, Gammoh N & Ryan KM (2023) Autophagy and autophagy-related pathways in cancer. Nature Reviews Molecular Cell Biology, 24(8), 560–575. https://doi.org/10.1038/s41580-023-00585-z
108. Thorburn A, Thamm DH & Gustafson DL (2014) Autophagy and cancer therapy. Molecular Pharmacology, 85(6), 830–838. https://doi.org/10.1124/mol.114.091850
109. Mulcahy Levy JM & Thorburn A (2020) Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death and Differentiation, 27(3), 843–857. https://doi.org/10.1038/s41418-019-0474-7
110. Carter ME & de Lecea L (2011) Optogenetic investigation of neural circuits in vivo. Trends in Molecular Medicine, 17(4), 197–206. https://doi.org/10.1016/j.molmed.2010.12.005
111. Cao ZF, Burdakov D & Sarnyai Z (2011) Optogenetics: potentials for addiction research. Addiction Biology, 16(4), 519–531. https://doi.org/10.1111/j.1369-1600.2011.00386.x
112. Fenno L, Yizhar O & Deisseroth K (2011) The development and application of optogenetics. Annual Review of Neuroscience, 34, 389–412. https://doi.org/10.1146/annurev-neuro-061010-113817
113. Zhang F, Vierock J, Yizhar O, Fenno LE, Tsunoda S, Kianianmomeni A, Prigge M, Berndt A, Cushman J, Polle J, Magnuson J, Hegemann P & Deisseroth K (2011) The microbial opsin family of optogenetic tools. Cell, 147(7), 1446–1457. https://doi.org/10.1016/j.cell.2011.12.004
114. Deisseroth K (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nature Neuroscience, 18(9), 1213–1225. https://doi.org/10.1038/nn.4091
115. Nagel G, Szellas T, Huhn W, Kateriya S, Adeishvili N, Berthold P, Ollig D, Hegemann P & Bamberg E (2003) Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proceedings of the National Academy of Sciences. 100 (24) ,13940–13945, https://doi.org/10.1073/pnas.1936192100
116. Foutz TJ, Arlow RL & McIntyre CC (2012) Theoretical principles underlying optical stimulation of a channelrhodopsin-2 positive pyramidal neuron. Journal of Neurophysiology, 107(12), 3235–3245. https://doi.org/10.1152/jn.00501.2011
117. Kleinlogel S, Feldbauer K, Dempski RE, Fotis H, Wood PG, Bamann C & Bamberg E (2011) Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh. Nature Neuroscience, 14(4), 513–518. https://doi.org/10.1038/nn.2776
118. Smedler E & Uhlén P (2014) Frequency decoding of calcium oscillations. Biochimica et Biophysica Acta, 1840(3), 964–969. https://doi.org/10.1016/j.bbagen.2013.11.015
119. Plotnikova OV, Pugacheva EN & Golemis EA (2009) Primary cilia and the cell cycle. Methods in Cell Biology, 94, 137–160. https://doi.org/10.1016/S0091-679X(08)94007-3
120. Carafoli E, Santella L, Branca D & Brini M (2001) Generation, control, and processing of cellular calcium signals. Critical Reviews in Biochemistry and Molecular Biology, 36(2), 107–260. https://doi.org/10.1080/20014091074183
121. Pinto MC, Kihara AH, Goulart VA, Tonelli FM, Gomes KN, Ulrich H & Resende RR (2015) Calcium signaling and cell proliferation. Cellular Signalling, 27(11), 2139–2149. https://doi.org/10.1016/j.cellsig.2015.08.006
122. Delling M, DeCaen PG, Doerner JF, Febvay S & Clapham DE (2013) Primary cilia are specialized calcium signalling organelles. Nature, 504(7479), 311–314. https://doi.org/10.1038/nature12833
123. Tojyo Y, Morita T, Nezu A & Tanimura A (2014) Key components of store-operated Ca2+ entry in non-excitable cells. Journal of Pharmacological Sciences, 125(4), 340–346. https://doi.org/10.1254/jphs.14r06cp
124. Bonilla IM, Belevych AE, Baine S, Stepanov A, Mezache L, Bodnar T, Liu B, Volpe P, Priori S, Weisleder N, Sakuta G, Carnes CA, Radwański PB, Veeraraghavan R & Gyorke S (2019) Enhancement of cardiac store operated calcium entry (SOCE) within novel intercalated disk microdomains in arrhythmic disease. Scientific Reports, 9(1), 10179. https://doi.org/10.1038/s41598-019-46427-x
125. Plotnikova OV, Nikonova AS, Loskutov YV, Kozyulina PY, Pugacheva EN & Golemis EA (2012) Calmodulin activation of Aurora-A kinase (AURKA) is required during ciliary disassembly and in mitosis. Molecular Biology of the Cell, 23(14), 2658–2670. https://doi.org/10.1091/mbc.E11-12-1056
126. Korobeynikov V, Deneka AY & Golemis EA (2017) Mechanisms for nonmitotic activation of Aurora-A at cilia. Biochemical Society Transactions, 45(1), 37–49. https://doi.org/10.1042/BST20160142
127. Kania E, Pająk B & Orzechowski A (2015) Calcium homeostasis and ER stress in control of autophagy in cancer cells. BioMed Research International, 2015, 352794. https://doi.org/10.1155/2015/352794
128. Patergnani S, Danese A, Bouhamida E, Aguiari G, Previati M, Pinton P & Giorgi C (2020) Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer. International Journal of Molecular Sciences, 21(21), 8323. https://doi.org/10.3390/ijms21218323
129. Huang Q, Cao H, Zhan L, Sun X, Wang G, Li J, Guo X, Ren T, Wang Z, Lyu Y, Liu B, An J & Xing J (2017) Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Cancer Letters, 403, 108–118. https://doi.org/10.1016/j.canlet.2017.05.034
130. Yu Z, Wang H, Tang W, Wang S, Tian X, Zhu Y & He H (2021) Mitochondrial Ca2+ oscillation induces mitophagy initiation through the PINK1-Parkin pathway. Cell Death and Disease, 12(7), 632. https://doi.org/10.1038/s41419-021-03913-3
131. Levin-Salomon V, Bialik S & Kimchi A (2014) DAP-kinase and autophagy. Apoptosis, 19(2), 346–356. https://doi.org/10.1007/s10495-013-0918-3
132. Jing Z, He X, Jia Z, Sa Y, Yang B & Liu P (2021) NCAPD2 inhibits autophagy by regulating Ca2+/CAMKK2/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis to promote colorectal cancer. Cancer Letters, 520, 26–37. https://doi.org/10.1016/j.canlet.2021.06.029
133. Déliot N & Constantin B (2015) Plasma membrane calcium channels in cancer: alterations and consequences for cell proliferation and migration. Biochimica et Biophysica Acta, 1848(10 Pt B), 2512–2522. https://doi.org/10.1016/j.bbamem.2015.06.009
134. Tu MK, Levin JB, Hamilton AM & Borodinsky LN (2016) Calcium signaling in skeletal muscle development, maintenance and regeneration. Cell Calcium, 59(2–3), 91–97. https://doi.org/10.1016/j.ceca.2016.02.005
135. Danese A, Leo S, Rimessi A, Wieckowski MR, Fiorica F, Giorgi C & Pinton P (2021) Cell death as a result of calcium signaling modulation: A cancer-centric prospective. Biochimica et Biophysica Acta. Molecular Cell Research, 1868(8), 119061. https://doi.org/10.1016/j.bbamcr.2021.119061
136. Kerkhofs M, Bittremieux M, Morciano G, Giorgi C, Pinton P, Parys JB & Bultynck G (2018) Emerging molecular mechanisms in chemotherapy: Ca2+ signaling at the mitochondria-associated endoplasmic reticulum membranes. Cell Death and Disease, 9(3), 334. https://doi.org/10.1038/s41419-017-0179-0
137. Trump BF & Berezesky IK (1995) Calcium-mediated cell injury and cell death. The FASEB Journal, 9(2), 219–228. https://doi.org/10.1096/fasebj.9.2.7781924
138. Liu X, Rothe K, Yen R, Fruhstorfer C, Maetzig T, Chen M, Forrest DL, Humphries RK & Jiang X (2017) A novel AHI-1-BCR-ABL-DNM2 complex regulates leukemic properties of primitive CML cells through enhanced cellular endocytosis and ROS-mediated autophagy. Leukemia, 31(11), 2376–2387. https://doi.org/10.1038/leu.2017.108
139. Muñoz-Estrada J & Ferland RJ (2019) Ahi1 promotes Arl13b ciliary recruitment, regulates Arl13b stability and is required for normal cell migration. Journal of Cell Science, 132(17), jcs230680. https://doi.org/10.1242/jcs.230680
140. Wang S, Livingston MJ, Su Y & Dong Z (2015) Reciprocal regulation of cilia and autophagy via the MTOR and proteasome pathways. Autophagy, 11(4), 607–616. https://doi.org/10.1080/15548627.2015.1023983
141. Akhshi T & Trimble WS (2021) A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy. The Journal of Cell Biology, 220(1), e202004179. https://doi.org/10.1083/jcb.202004179
142. Lorzadeh S, Kohan L, Ghavami S & Azarpira N (2021) Autophagy and the Wnt signaling pathway: A focus on Wnt/β-catenin signaling. Biochimica et Biophysica Acta. Molecular Cell Research, 1868(3), 118926. https://doi.org/10.1016/j.bbamcr.2020.118926
143. Orhon I, Dupont N, Pampliega O, Cuervo AM & Codogno P (2015) Autophagy and regulation of cilia function and assembly. Cell Death and Differentiation, 22(3), 389–397. https://doi.org/10.1038/cdd.2014.171
144. Morleo M, Brillante S, Formisano U, Ferrante L, Carbone F, Iaconis D, Palma A, Buonomo V, Maione AS, Grumati P, Settembre C & Franco B (2021) Regulation of autophagosome biogenesis by OFD1-mediated selective autophagy. The EMBO Journal, 40(4), e105120. https://doi.org/10.15252/embj.2020105120