Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes

Xiao,Fang; Li,Yanhong; Dai,Lu; Deng,Yuanyuan; Zou,Yue; Li,Peng; Yang,Yuan; Zhong,Caigao

doi:10.3892/ijmm.2012.1031

Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes

Authors:
- Fang Xiao
- Yanhong Li
- Lu Dai
- Yuanyuan Deng
- Yue Zou
- Peng Li
- Yuan Yang
- Caigao Zhong
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Affiliations: Department of Health Toxicology, School of Public Health, Central South University, Changsha 410078, P.R. China
Published online on: June 14, 2012 https://doi.org/10.3892/ijmm.2012.1031
Pages: 629-635

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Abstract

Hexavalent chromium [Cr(VI)], which is used for various industrial applications, such as leather tanning and chroming, can cause a number of human diseases including inflammation and cancer. Cr(VI) exposure leads to severe damage to the liver, but the mechanisms involved in Cr(VI)-mediated toxicity in the liver are unclear. The present study provides evidence that Cr(VI) enhances reactive oxygen species (ROS) accumulation by inhibiting the mitochondrial respiratory chain complex (MRCC) I. Cr(VI) did not affect the expression levels of antioxidative proteins such as superoxide dismutase (SOD), catalase and thioredoxin (Trx), indicating that the antioxidative system was not involved in Cr(VI)-induced ROS accumulation. We found that ROS mediated caspase-3 activation partially depends on the downregulation of the heat shock protein (HSP) 70 and 90. In order to confirm our hypothesis that ROS plays a key role in Cr(VI)-mediated cytotoxicity, we used N-acetylcysteine (NAC) to inhibit the accumulation of ROS. NAC successfully blocked the inhibition of HSP70 and HSP90 as well as the activation of caspase-3, suggesting that ROS is essential in Cr(VI)-induced caspase-3 activation. By applying different MRCC substrates as electron donors, we also confirmed that Cr(VI) could accept the electrons leaked from MRCC I and the reduction occurs at MRCC I. In conclusion, the present study demonstrates that Cr(VI) induces ROS-dependent caspase-3 activation by inhibiting MRCC I activity, and MRCC I has been identified as a new target and a new mechanism for the apoptosis-inducing activity displayed by Cr(VI).

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1.	J BarnhartOccurrences, uses, and properties of chromiumRegul Toxicol Pharmacol26S3S7199710.1006/rtph.1997.11329380835
2.	BD KergerDJ PaustenbachGE CorbettBL FinleyAbsorption and elimination of trivalent and hexavalent chromium in humans following ingestion of a bolus dose in drinking waterToxicol Appl Pharmacol141145158199610.1016/S0041-008X(96)80020-28917687
3.	J YeX ShiGene expression profile in response to chromium-induced cell stress in A549 cellsMol Cell Biochem222189197200110.1023/A:101797441505211678601
4.	K ChoureyMR ThompsonJ Morrell-FalveyGlobal molecular and morphological effects of 24-hour chromium(VI) exposure on Shewanella oneidensis MR-1Appl Environ Microbiol7263316344200610.1128/AEM.00813-0616957260
5.	PH ConnettKE WetterhahnMetabolism of the carcinogen chromate by cellular constituentsStructures and Bonding Inorganic Elements in BiochemistrySpringer-VerlagBerlin93124198310.1007/BFb0111319
6.	X ShiA ChiuCT ChenReduction of chromium (VI) and its relationship to carcinogenesisJ Toxicol Environ Health B Crit Rev287104199910.1080/10937409928124110081526
7.	P VenierA MontaldiF MajoneV BianchiAG LevisCytotoxic, mutagenic and clastogenic effects of industrial chromium compoundsCarcinogenesis313311338198210.1093/carcin/3.11.13316758977
8.	M GunaratnamMH GrantCr (VI) inhibits DNA, RNA and protein syntheses in hepatocytes: involvement of glutathione reductase, reduced glutathione and DT-diaphoraseToxicol In Vitro22879886200810.1016/j.tiv.2008.01.00518321676
9.	AI RafaelA AlmeidaP SantosA role for transforming growth factor-beta apoptotic signaling pathway in liver injury induced by ingestion of water contaminated with high levels of Cr(VI)Toxicol Appl Pharmacol224163173200710.1016/j.taap.2007.07.00417692352
10.	Z UngvariBF KrasnikovA CsiszarTesting hypotheses of aging in long-lived mice of the genus Peromyscus: association between longevity and mitochondrial stress resistance, ROS detoxification pathways, and DNA repair efficiencyAge (Dordr)30121133200810.1007/s11357-008-9059-y
11.	RO PoytonKA BallPR CastelloMitochondrial generation of free radicals and hypoxic signalingTrends Endocrinol Metab20332340200910.1016/j.tem.2009.04.00119733481
12.	SK YonallyRA CapaldiThe F(1)F(0) ATP synthase and mitochondrial respiratory chain complexes are present on the plasma membrane of an osteosarcoma cell line: An immunocytochemical studyMitochondrion6305314200610.1016/j.mito.2006.10.001
13.	N DiasC BaillyDrugs targeting mitochondrial functions to control tumor cell growthBiochem Pharmacol70112200510.1016/j.bcp.2005.03.02115907809
14.	W XuL NgoG PerezM DokmanovicPA MarksIntrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitorProc Natl Acad Sci USA1031554015545200610.1073/pnas.060751810317030815
15.	M InoueEF SatoM NishikawaMitochondrial generation of reactive oxygen species and its role in aerobic lifeCurr Med Chem1024952505200310.2174/092986703345647714529465
16.	MP WaalkesDA FoxSR PatiernoMJ McCabeMetals and disorders of cell accumulation: modulation of apoptosis and cell proliferationToxicol Sci56255261200010.1093/toxsci/56.2.25510910982
17.	A GhelliC ZannaAM PorcelliLeber’s hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose mediumJ Biol Chem278414541502003
18.	J Cinatl JrJ CinatlPH DrieverSodium valproate inhibits in vivo growth of human neuroblastoma cellsAnticancer Drugs8958963199710.1097/00001813-199711000-000079436639
19.	N BrustovetskyT BrustovetskyR JemmersonJM DubinskyCalcium-induced Cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membraneJ Neurochem80207218200210.1046/j.0022-3042.2001.00671.x11902111
20.	D RybergJ AlexanderInhibitory action of hexavalent chromium (Cr(VI)) on the mitochondrial respiration and a possible coupling to the reduction of Cr(VI)Biochem Pharmacol3324612466198410.1016/0006-2952(84)90718-46466363
21.	A ArilloF MelodiaR FracheReduction of hexavalent chromium by mitochondria: methodological implications and possible mechanismsEcotoxicol Environ Saf14164177198710.1016/0147-6513(87)90059-53691371
22.	MC KamradtF ChenVL CrynsThe small heat shock protein alpha B-crystallin negatively regulates cytochrome cand caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturationJ Biol Chem2761605916063200110.1074/jbc.C100107200
23.	JA RibeilY ZermatiJ VandekerckhoveHsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1Nature445102105200710.1038/nature0537817167422
24.	DL CarlisleDE PritchardJ SinghSR PatiernoChromium (VI) induces p53-dependent apoptosis in diploid human lung and mouse dermal fibroblastsMol Carcinog28111118200010.1002/1098-2744(200006)28:2%3C111::AID-MC7%3E3.0.CO;2-Y10900468
25.	XF WangML XingY ShenX ZhuLH XuOral administration of Cr (VI) induced oxidative stress, DNA damage and apoptotic cell death in miceToxicology2281623200610.1016/j.tox.2006.08.00516979809
26.	DC WallaceMitochondrial diseases in man and mouseScience28314821488199910.1126/science.283.5407.148210066162
27.	KN IslamY KayanokiH KanetoTGF-beta1 triggers oxidative modifications and enhances apoptosis in HIT cells through accumulation of reactive oxygen species by suppression of catalase and glutathione peroxidaseFree Radic Biol Med2210071017199710.1016/S0891-5849(96)00493-5
28.	W WangM AdachiR KawamuraParthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activityApoptosis1122252235200610.1007/s10495-006-0287-2
29.	N LiK RaghebG LawlerMitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species productionJ Biol Chem27885168525200310.1074/jbc.M210432200
30.	XL ShiNS DalalEvidence for a Fenton-type mechanism for the generation of .OH radicals in the reduction of Cr(VI) in cellular mediaArch Biochem Biophys2819095199010.1016/0003-9861(90)90417-W2166480
31.	J WaltersC PopFL ScottA constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosisBiochem J424335345200910.1042/BJ2009082519788411
32.	AW Abu-QareMB Abou-DoniaBiomarkers of apoptosis: release of cytochrome c, activation of caspase-3, induction of 8-hydroxy-2′-deoxyguanosine, increased 3-nitrotyrosine, and alteration of p53 geneJ Toxicol Environ Health B Crit Rev4313332200111503418
33.	E PaitelR FahraeusF CheclerCellular prion protein sensitizes neurons to apoptotic stimuli through Mdm2-regulated and p53-dependent caspase-3-like activationJ Biol Chem2781006110066200310.1074/jbc.M21158020012529324
34.	A De MaioHeat shock proteins: facts, thoughts, and dreamsShock111121999
35.	HM BeereBB WolfK CainHeat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosomeNat Cell Biol2469475200010.1038/3501950110934466