Abstract
It is generally believed that gene-environment interaction may contribute to neurodegeneration. Of particular note is that iron overload may be one of the risk factors for neurodegeneration. However, the mechanisms underlying iron-associated neurotoxicity are not fully understood. Here we explored the effects of mechanistic target of rapamycin (mTOR) inhibition in iron-stressed human neuroblastoma cells. Two mTOR inhibitors, rapamycin and Torin 1, had similar effects in cells exposed to a relatively low concentration of iron. At a higher concentration of iron, Torin 1, instead of rapamycin, could further aggravate iron-induced cytotoxicity, and mitochondrial ROS levels were significantly higher in Torin 1-treated cells. These results suggest that mTOR inhibition may not be able to alleviate iron-induced neurotoxicity.
References
Ascherio A, Schwarzschild MA (2016) The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15:1255–1270
Ayton S, Lei P (2014) Nigral iron elevation is an invariable feature of Parkinson’s disease and is a sufficient cause of neurodegeneration. Biomed Res Int 2014:581256
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306
Cheng P, Yu J, Huang W, Bai S, Zhu X, Qi Z, Shao W, Xie P (2015) Dietary intake of iron, zinc, copper, and risk of Parkinson’s disease: a meta-analysis. Neurol Sci 36:2269–2275
Choi KC, Kim SH, Ha JY, Kim ST, Son JH (2010) A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. J Neurochem 112:366–376
Decressac M, Bjorklund A (2013) mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats. J Parkinsons Dis 3:13–17
Duck KA, Connor JR (2016) Iron uptake and transport across physiological barriers. Biometals 29:573–591
Farshbaf MJ, Ghaedi K (2017) Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders? Biometals 30:1–16
Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Kortsha GX, Brown GG, Richardson RJ (1999) Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology 20:239–247
Gotz ME, Double K, Gerlach M, Youdim MB, Riederer P (2004) The relevance of iron in the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 1012:193–208
Hare DJ, Arora M, Jenkins NL, Finkelstein DI, Doble PA, Bush AI (2015) Is early-life iron exposure critical in neurodegeneration? Nat Rev Neurol 11:536–544
Hu Y, Lu HR, Zhang JC, Chen J, Chai ZF, Zhang JX (2014) Essential role of AKT in tumor cells addicted to FGFR. Anticancer Drugs 25:183–188
Huang H, Chen J, Lu HR, Zhou MX, Chai ZF, Hu Y (2017) Iron-induced generation of mitochondrial ROS depends on AMPK activity. Biometals 30:623–628
Johnson CC, Gorell JM, Rybicki BA, Sanders K, Peterson EL (1999) Adult nutrient intake as a risk factor for Parkinson’s disease. Int J Epidemiol 28:1102–1109
Lan AP, Chen J, Chai ZF, Hu Y (2016a) The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms. Biometals 29:665–678
Lan AP, Xiong XJ, Chen J, Wang X, Chai ZF, Hu Y (2016b) AMPK inhibition enhances the neurotoxicity of Cu(II) in SH-SY5Y cells. Neurotox Res 30:499–509
Lan AP, Chen J, Zhao YL, Chai ZF, Hu Y (2017) mTOR signaling in Parkinson’s disease. NeuroMol Med 19:1–10
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293
Liu J, Hu Y, Waller DL, Wang JF, Liu QS (2012) Natural products as kinase inhibitors. Nat Prod Rep 29:392–403
Logroscino G, Gao X, Chen H, Wing A, Ascherio A (2008) Dietary iron intake and risk of Parkinson’s disease. Am J Epidemiol 168:1381–1388
Lu HR, Li SH, Chen J, Xia J, Zhang JC, Huang Y, Liu XX, Wu HC, Zhao YL, Chai ZF, Hu Y (2015) Metal ions modulate the conformation and stability of a G-quadruplex with or without a small-molecule ligand. Metallomics 7:1508–1514
Lu HR, Chen J, Huang H, Zhou MX, Zhu Q, Yao SQ, Chai ZF, Hu Y (2017) Iron modulates the activity of monoamine oxidase B in SH-SY5Y cells. Biometals 30:599–607
Miyake Y, Tanaka K, Fukushima W, Sasaki S, Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T, Kawamura N, Sakae N, Fukuyama H, Hirota Y, Nagai M, Fukuoka Kinki Parkinson’s Disease Study G (2011) Dietary intake of metals and risk of Parkinson’s disease: a case-control study in Japan. J Neurol Sci 306:98–102
Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2003) Parkinson’s disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 60:1761–1766
Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, Checkoway H (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease. Parkinsonism Relat Disord 15:47–52
Pyatigorskaya N, Sharman M, Corvol JC, Valabregue R, Yahia-Cherif L, Poupon F, Cormier-Dequaire F, Siebner H, Klebe S, Vidailhet M, Brice A, Lehericy S (2015) High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2*relaxometry. Mov Disord 30:1077–1084
Santini E, Heiman M, Greengard P, Valjent E, Fisone G (2009) Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Sci Signal 2:ra36
Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29:13578–13588
Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ (2009) Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci 12:1129–1135
Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023–8032
Wang JY, Zhuang QQ, Zhu LB, Zhu H, Li T, Li R, Chen SF, Huang CP, Zhang X, Zhu JH (2016) Meta-analysis of brain iron levels of Parkinson’s disease patients determined by postmortem and MRI measurements. Sci Rep 6:36669
Wieler M, Gee M, Camicioli R, Martin WRW (2016) Freezing of gait in early Parkinson’s disease: nigral iron content estimated from magnetic resonance imaging. J Neurol Sci 361:87–91
Acknowledgements
We acknowledge the financial support from National Natural Science Foundation of China (Grant No. 11375213, 21390411), the Hundred Talents Program of the Chinese Academy of Sciences and IHEP Innovation Program.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Huang, H., Chen, J., Lu, H. et al. Two mTOR inhibitors, rapamycin and Torin 1, differentially regulate iron-induced generation of mitochondrial ROS. Biometals 30, 975–980 (2017). https://doi.org/10.1007/s10534-017-0059-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10534-017-0059-1