Restricted accessResearch articleFirst published online 2013-01
Mitochondrial Ferritin Attenuates β -Amyloid-Induced Neurotoxicity: Reduction in Oxidative Damage Through the Erk/P38 Mitogen-Activated Protein Kinase Pathways
Aims: Mitochondrial ferritin (MtFt), which was recently discovered, plays an important role in preventing neuronal damage in 6-hydroxydopamine-induced Parkinsonism by maintaining mitochondrial iron homeostasis. Disruption of iron regulation also plays a key role in the etiology of Alzheimer's disease (AD). To explore the potential neuroprotective roles of MtFt, rats and cells were treated with Aβ25–35 to establish an AD model. Results: We report that knockdown of MtFt expression significantly enhanced Aβ25–35-induced neurotoxicity as shown by dysregulation of iron homeostasis, enhanced oxidative stress, and increased cell apoptosis. Opposite results were obtained when MtFt was overexpressed in SH-SY5Y cells prior to treatment with Aβ25–35. Further, MtFt inhibited Aβ25–35-induced P38 mitogen-activated protein kinase and activated extracellular signal-regulated kinase (Erk) signaling. Innovation: MtFt attenuated Aβ25–35-induced neurotoxicity and reduced oxidative damage through Erk/P38 kinase signaling. Conclusion: Our results show a protective role of MtFt in AD and suggest that regulation of MtFt expression in neuronal cells may provide a new neuroprotective strategy for AD. Antioxid. Redox Signal. 18, 158–169.
Get full access to this article
View all access options for this article.
References
1.
ArosioP, LeviS. Ferritin, iron homeostasis, and oxidative damage. Free Radic Biol Med, 33:457–463. 2002.
2.
BassDA, ParceJW, DechateletLR, SzejdaP, SeedsMC, ThomasM. Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol, 130:1910–1917. 1983.
3.
BushAI, TanziRE. Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics, 5:421–432. 2008.
ChenL, LiuL, YinJ, LuoY, HuangS. Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol, 41:1284–1295. 2009.
6.
ChiuWT, ShenSC, YangLY, ChowJM, WuCY, ChenYC. Inhibition of HSP90-dependent telomerase activity in amyloid beta-induced apoptosis of cerebral endothelial cells. J Cell Physiol, 226:2041–2051. 2011.
7.
ChongthammakunV, SanvarindaY, ChongthammakunS. Reactive oxygen species production and MAPK activation are implicated in tetrahydrobiopterin-induced SH-SY5Y cell death. Neurosci Lett, 449:178–182. 2009.
8.
EatonJW, QianM. Molecular bases of cellular iron toxicity. Free Radic Biol Med, 32:833–840. 2002.
9.
GoodsellDS. The molecular perspective: cytochrome C and apoptosis. Stem Cells, 22:428–429. 2004.
10.
HayashiT, TsaoLI, SuTP. Antiapoptotic and cytotoxic properties of delta opioid peptide [D-Ala(2),D-Leu(5)]enkephalin in PC12 cells. Synapse, 43:86–94. 2002.
KeilU, BonertA, MarquesCA, ScherpingI, WeyermannJ, StrosznajderJB, Muller-SpahnF, HaassC, CzechC, PradierL, MullerWE, EckertA. Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem, 279:50310–50320. 2004.
13.
KimTI, LeeYK, ParkSG, ChoiIS, BanJO, ParkHK, NamSY, YunYW, HanSB, OhKW, HongJT. l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med, 47:1601–1610. 2009.
14.
Langlois d'EstaintotB, SantambrogioP, GranierT, GalloisB, ChevalierJM, PrecigouxG, LeviS, ArosioP. Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. J Mol Biol, 340:277–293. 2004.
15.
LeviS, CorsiB, BosisioM, InvernizziR, VolzA, SanfordD, ArosioP, DrysdaleJ. A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem, 276:24437–24440. 2001.
MancusoC, ScapaginiG, CurroD, Giuffrida StellaAM, De MarcoC, ButterfieldDA, CalabreseV. Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci, 12:1107–1123. 2007.
18.
MorimotoK, YoshimiK, TonohiroT, YamadaN, OdaT, KanekoI. Co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons. Neuroscience, 84:479–487. 1998.
19.
MoriscoC, MarroneC, TrimarcoV, CrispoS, MontiMG, SadoshimaJ, TrimarcoB. Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression. Cardiovasc Res, 76:453–464. 2007.
20.
MorrisCM, KerwinJM, EdwardsonJA. Non-haem iron histochemistry of the normal and Alzheimer's disease hippocampus. Neurodegeneration, 3:267–275. 1994.
21.
NieG, ChenG, SheftelAD, PantopoulosK, PonkaP. In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin. Blood, 108:2428–2434. 2006.
22.
NieG, SheftelAD, KimSF, PonkaP. Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood, 105:2161–2167. 2005.
23.
RolstonRK, PerryG, ZhuX, CastellaniRJ, DwyerBE, LeeHG, PetersenRB, SmithMA. Iron: a pathological mediator of Alzheimer disease?Agro Food Ind Hi Tech, 19:33–36. 2009.
24.
SelkoeDJ. Amyloid beta-protein and the genetics of Alzheimer's disease. J Biol Chem, 271:18295–18298. 1996.
25.
SelkoeDJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci, 924:17–25. 2000.
TortosaA, LopezE, FerrerI. Bcl-2 and Bax proteins in Lewy bodies from patients with Parkinson's disease and diffuse Lewy body disease. Neurosci Lett, 238:78–80. 1997.
32.
TrubetskayaVV, StepanichevMY, OnufrievMV, LazarevaNA, MarkevichVA, GulyaevaNV. Administration of aggregated beta-amyloid peptide (25–35) induces changes in long-term potentiation in the hippocampus in vivo. Neurosci Behav Physiol, 33:95–98. 2003.
33.
UmedaT, TomiyamaT, SakamaN, TanakaS, LambertMP, KleinWL, MoriH. Intraneuronal amyloid beta oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. J Neurosci Res, 89:1031–1042. 2011.
34.
WangL, YangH, ZhaoS, SatoH, KonishiY, BeachTG, AbdelalimEM, BisemNJ, TooyamaI. Expression and localization of mitochondrial ferritin mRNA in Alzheimer's disease cerebral cortex. PLoS One, 6:e22325. 2011.
35.
WeisSN, PettenuzzoLF, KrolowR, ValentimLM, MotaCS, DalmazC, WyseAT, NettoCA. Neonatal hypoxia-ischemia induces sex-related changes in rat brain mitochondria. Mitochondrion, 12:271–279. 2011.
36.
WhiteFA, Keller-PeckCR, KnudsonCM, KorsmeyerSJ, SniderWD. Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J Neurosci, 18:1428–1439. 1998.
37.
YangZH, SunK, SuoWH, YaoLY, FuQ, CuiYY, FuGH, ChenHZ, LuY. N-stearoyltyrosine protects primary neurons from Abeta-induced apoptosis through modulating mitogen-activated protein kinase activity. Neuroscience, 169:1840–1847. 2011.
38.
YanknerBA, DuffyLK, KirschnerDA. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science, 250:279–282. 1990.
ZhangR, WangZ, HowsonPA, XiaZ, ZhouS, WuE, XiaZ, HuY. Smilagenin attenuates beta amyloid (25–35)-induced degeneration of neuronal cells via stimulating the gene expression of brain-derived neurotrophic factor. Neuroscience, 210:275–285. 2012.
41.
ZhangY, ZhaoB. Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. J Neurochem, 86:1189–1200. 2003.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
