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How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale

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Abstract

Metal pollutants are a global health risk due to their ability to contribute to a variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is implicated in anemia, osteomalacia, hepatic disorder, and neurological disorder. In this review, we outline how this intracellular generator of reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished mitochondrial activity, anerobiosis, and the channeling of α-ketoacids towards anti-oxidant defense. The resulting metabolic reconfiguration leads to fat accumulation and a reduction in ATP synthesis, characteristics that are common to numerous medical disorders. Hence, the ability of Al toxicity to create an oxidative environment promotes dysfunctional metabolic processes in astrocytes and hepatocytes. These molecular events triggered by Al-induced ROS production are the potential mediators of brain and liver disorders.

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Abbreviations

BADH:

Betaine-aldehyde dehydrogenase

BBDOX:

γ-butyrobetaine dioxygenase

ETC:

Electron transport chain

HDL:

High-density lipoprotein

HIF:

Hypoxia-inducible factor

HTML:

3-hydroxy-N 6-trimethyllysine

ICDH:

Isocitrate dehydrogenase

KGDH:

Alpha-ketoglutarate dehydrogenase

LDL:

Low-density lipoprotein

MDH:

Malate dehydrogenase

PHD:

Prolyl hydroxylase

ROS:

Reactive oxygen species

TCA:

Tricarboxylic acid

TML:

N 6-trimethyllysine

TMLD:

Trimethyllysine dioxygenase

VLDL:

Very-low-density lipoprotein

References

  • Adibhatla RM, Hatcher JF. Altered lipid metabolism in brain injury and disorders lipids in health and disease. In: Quinn PJ, Wang X, editors. Springer, Dordrecht; 2008.

  • Barnard CG, McBride DI, Firth HM, Herbison GP. Assessing individual employee risk factors for occupational asthma in primary aluminium smelting. Occup Environ Med. 2004;61:604–8.

    Article  PubMed  CAS  Google Scholar 

  • Becaria A, Lahiri DK, Bondy SC, Chen D, Hamadeh A, Li H, et al. Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain. J Neuroimmunol. 2006;176:16–23.

    Article  PubMed  CAS  Google Scholar 

  • Bhasin P, Singla N, Dhawan DK. Protective role of zinc during aluminum-induced hepatotoxicity. Environ Toxicol. 2012. doi:10.1002/tox.21760.

  • Bignucolo A, Lemire J, Auger C, Castonguay Z, Appanna V, Appanna VD. The molecular connection between aluminum toxicity, anemia, inflammation and obesity: therapeutic cues. In: Silverberg DD, editor. Anemia: InTech; 2012.

  • Bosetti F, Solaini G, Tendi EA, Chikhale EG, Chandrasekaran K, Rapoport SI. Mitochondrial cytochrome c oxidase subunit III is selectively down-regulated by aluminum exposure in PC12S cells. Neuroreport. 2001;12:721–4.

    Article  PubMed  CAS  Google Scholar 

  • Buchman AL, Iyer K, Fryer J. Parenteral nutrition–associated liver disease and the role for isolated intestine and intestine/liver transplantation. Hepatology. 2006;43:9–19.

    Article  PubMed  Google Scholar 

  • Candan N, Tuzmen N. Very rapid quantification of malondialdehyde (MDA) in rat brain exposed to lead, aluminium and phenolic antioxidants by high-performance liquid chromatography-fluorescence detection. Neurotoxicology. 2008;29:708–13.

    Article  PubMed  CAS  Google Scholar 

  • Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. 2000;71:621s–9s.

    PubMed  CAS  Google Scholar 

  • Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush AI. Metal chelation as a potential therapy for Alzheimer's disease. Ann N Y Acad Sci. 2000;920:292–304.

    Article  PubMed  CAS  Google Scholar 

  • De Marchi U, Mancon M, Battaglia V, Ceccon S, Cardellini P, Toninello A. Influence of reactive oxygen species production by monoamine oxidase activity on aluminum-induced mitochondrial permeability transition. Cell Mol Life Sci. 2004;61:2664–71.

    Article  PubMed  Google Scholar 

  • Exley C. A biogeochemical cycle for aluminium? J Inorg Biochem. 2003;97:1–7.

    Article  PubMed  CAS  Google Scholar 

  • Exley C. Darwin, natural selection and the biological essentiality of aluminium and silicon. Trends Biochem Sci. 2009;34:589–93.

    Article  PubMed  CAS  Google Scholar 

  • Ferreira PC, Piai KdA, Takayanagui AMM, Segura-Muñoz SI. Aluminum as a risk factor for Alzheimer's disease. Rev Lat Am Enfermagem. 2008;16:151–7.

    Article  PubMed  Google Scholar 

  • Ferretti G, Marchionni C, Bacchetti T, Galeazzi T, Dousset N. Effect of aluminium on lipid peroxidation of human high density lipoproteins. Free Radic Res. 2003;37:515–21.

    Article  PubMed  CAS  Google Scholar 

  • Flaten TP. Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water. Brain Res Bull. 2001;55:187–96.

    Article  PubMed  CAS  Google Scholar 

  • Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117:4425–33.

    Article  PubMed  CAS  Google Scholar 

  • Gao X, Wu J, Dong Z, Hua C, Hu H, Mei C. A low-protein diet supplemented with ketoacids plays a more protective role against oxidative stress of rat kidney tissue with 5/6 nephrectomy than a low-protein alone. Br J Nutr. 2009;103:608–16.

    Article  PubMed  Google Scholar 

  • Gómez M, Esparza JL, Cabré M, García T, Domingo JL. Aluminum exposure through the diet: metal levels in Amyloid βPP transgenic mice, a model for Alzheimer's disease. Toxicology. 2008;249:214–9.

    Article  PubMed  Google Scholar 

  • González M, Bernal C, Mahieu S, Carrillo M. The interactions between the chronic exposure to aluminum and liver regeneration on bile flow and organic anion transport in rats. Biol Trace Elem Res. 2009;127:164–76.

    Article  PubMed  Google Scholar 

  • Gorell JM, Peterson EL, Rybicki BA, Johnson CC. Multiple risk factors for Parkinson's disease. J Neurol Sci. 2004;217:169–74.

    Article  PubMed  Google Scholar 

  • Guo C-H, Hsu G-SW, Chuang C-J, Chen P-C. Aluminum accumulation induced testicular oxidative stress and altered selenium metabolism in mice. Environ Toxicol Pharmacol. 2009;27:176–81.

    Article  PubMed  CAS  Google Scholar 

  • Gura KM. Aluminum contamination in products used in parenteral nutrition: has anything changed? Nutrition. 2010;26:585–94.

    Article  PubMed  CAS  Google Scholar 

  • Harris WR, Berthon G, Day JP, Exley C, Pender T, William F, et al. Speciation of aluminium in biological systems. J Toxicol Environ Health. 1996;48:543–68.

    Article  PubMed  CAS  Google Scholar 

  • Hegde KR, Kovtun S, Varma SD. Induction of ultraviolet cataract in vitro: prevention by pyruvate. J Ocul Pharmacol Ther. 2007;23:492–502.

    Article  PubMed  CAS  Google Scholar 

  • Hung Y, Bush A, Cherny R. Copper in the brain and Alzheimer’s disease. J Biol Inorg Chem. 2010;15:61–76.

    Article  PubMed  CAS  Google Scholar 

  • Jeffery EH, Abreo K, Burgess E, Cannata J, Greger JL. Systemic aluminum toxicity: effects on bone, hematopoietic tissue and kidney. J Toxicol Environ Health. 1996;48:649–66.

    Article  PubMed  CAS  Google Scholar 

  • Kaizer RR, Corrêa MC, Spanevello RM, Morsch VM, Mazzanti CM, Gonçalves JF, et al. Acetylcholinesterase activation and enhanced lipid peroxidation after long-term exposure to low levels of aluminum on different mouse brain regions. J Inorg Biochem. 2005;99:1865–70.

    Article  PubMed  CAS  Google Scholar 

  • Kaneko N, Yasui H, Takada J, Suzuki K, Sakurai H. Orally administrated aluminum–maltolate complex enhances oxidative stress in the organs of mice. J Inorg Biochem. 2004;98:2022–31.

    Article  PubMed  CAS  Google Scholar 

  • Kaneko N, Sugioka T, Sakurai H. Aluminum compounds enhance lipid peroxidation in liposomes: Insight into cellular damage caused by oxidative stress. J Inorg Biochem. 2007;101:967–75.

    Article  PubMed  CAS  Google Scholar 

  • Kaur A, Joshi K, Minz RW, Gill KD. Neurofilament phosphorylation and disruption: a possible mechanism of chronic aluminium toxicity in Wistar rats. Toxicology. 2006;219:1–10.

    Article  PubMed  CAS  Google Scholar 

  • Kawahara M, Kato-Negishi M. Link between aluminum and the pathogenesis of Alzheimer's disease: the integration of the aluminum and Amyloid cascade hypothesis. Int J Alzheimer's Dis. 2011; 276393.

  • Kjellman UW, Björk K, Ekroth R, Karlsson H, Jagenburg R, Nilsson FN, et al. Addition of α-ketoglutarate to blood cardioplegia improves cardioprotection. Ann Thorac Surg. 1997;63:1625–33.

    Article  PubMed  CAS  Google Scholar 

  • Klein GL. Aluminum: new recognition of an old problem. Curr Opin Pharmacol. 2005;5:637–40.

    Article  PubMed  CAS  Google Scholar 

  • Krewski D, Yokel RA, Nieboer E, Borchelt D, Cohen J, Harry J, et al. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B. 2007;10:1–269.

    CAS  Google Scholar 

  • Kumar V, Bal A, Gill KD. Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminium. Brain Res. 2008;1232:94–103.

    Article  PubMed  CAS  Google Scholar 

  • Kumar V, Bal A, Gill KD. Susceptibility of mitochondrial superoxide dismutase to aluminium induced oxidative damage. Toxicology. 2009;255:117–23.

    Article  PubMed  CAS  Google Scholar 

  • Lemire J. A global metabolic perspective on aluminum toxicity in human astrocytes: Implications for neurological disorders. Ph.D, Laurentian University; 2011.

  • Lemire J, Mailloux R, Puiseux-Dao S, Appanna VD. Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells. J Neurosci Res. 2009;87:1474–83.

    Article  PubMed  CAS  Google Scholar 

  • Lemire J, Mailloux R, Darwich R, Auger C, Appanna VD. The disruption of l-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipidemia in human astrocytic and hepatic cells. Toxicol Lett. 2011;203:219–26.

    Article  PubMed  CAS  Google Scholar 

  • Li J, Bosch-Marce M, Nanayakkara A, Savransky V, Fried SK, Semenza GL, et al. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1α. Physiol Genomics. 2006;25:450–7.

    Article  PubMed  CAS  Google Scholar 

  • Li X, Han Y, Guan Y, Zhang L, Bai C & Li Y. Aluminum induces osteoblast apoptosis through the oxidative stress-mediated jnk signaling pathway. Biol Trace Elem Res. 2012; 1–7.

  • Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci. 1998;158:47–52.

    Article  PubMed  CAS  Google Scholar 

  • Lukiw WJ, Pogue AI. Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells. J Inorg Biochem. 2007;101:1265–9.

    Article  PubMed  CAS  Google Scholar 

  • Lukiw WJ, Percy ME, Kruck TP. Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture. J Inorg Biochem. 2005;99:1895–8.

    Article  PubMed  CAS  Google Scholar 

  • Mailloux RJ, Appanna VD. Aluminum toxicity triggers the nuclear translocation of HIF-1α and promotes anaerobiosis in hepatocytes. Toxicol In Vitro. 2007;21:16–24.

    Article  PubMed  CAS  Google Scholar 

  • Mailloux RJ, Hamel R, Appanna VD. Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes. J Biochem Mol Toxicol. 2006;20:198–208.

    Article  PubMed  CAS  Google Scholar 

  • Mailloux R, Lemire J, Appanna V. Aluminum-induced mitochondrial dysfunction leads to lipid accumulation in human hepatocytes: a link to obesity. Cell Physiol Biochem. 2007;20:627–38.

    Article  PubMed  CAS  Google Scholar 

  • Mailloux RJ, Puiseux-Dao S, Appanna VD. α-ketoglutarate abrogates the nuclear localization of HIF-1α in aluminum-exposed hepatocytes. Biochimie. 2009;91:408–15.

    Article  PubMed  CAS  Google Scholar 

  • Mailloux RJ, Lemire J, Appanna VD. Hepatic response to aluminum toxicity: dyslipidemia and liver diseases. Exp Cell Res. 2011;317:2231–8.

    Article  PubMed  CAS  Google Scholar 

  • Mallet RT, Sun J, Knott EM, Sharma AB, Olivencia-Yurvati AH. Metabolic cardioprotection by pyruvate: recent progress. Exp Biol Med. 2005;230:435–43.

    CAS  Google Scholar 

  • Middaugh J, Hamel R, Jean-Baptiste G, Beriault R, Chenier D, Appanna VD. Aluminum triggers decreased aconitase activity via Fe–S cluster disruption and the overexpression of isocitrate dehydrogenase and isocitrate lyase: a metabolic network mediating cellular survival. J Biol Chem. 2005;280:3159–65.

    Article  PubMed  CAS  Google Scholar 

  • Moulin JJ, Clavel T, Buclez B, Laffitte-Rigaud G. A mortality study among workers in a French aluminium reduction plant. Int Arch Occup Environ Health. 2000;73:323–30.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura H, Rose P, Blumer J, Reed M. Acute encephalopathy due to aluminum toxicity successfully treated by combined intravenous deferoxamine and hemodialysis. J Clin Pharmacol. 2000;40:296–300.

    Article  PubMed  CAS  Google Scholar 

  • Nayak P. Aluminum: impacts and disease. Environ Res. 2002;89:101–15.

    Article  PubMed  CAS  Google Scholar 

  • Nayak P, Sharma SB, Chowdary NV. Augmentation of aluminum-induced oxidative stress in rat cerebrum by presence of pro-oxidant (graded doses of ethanol) exposure. Neurochem Res. 2010;35:1681–90.

    Article  PubMed  CAS  Google Scholar 

  • Nehru B, Anand P. Oxidative damage following chronic aluminium exposure in adult and pup rat brains. J Trace Elem Med Biol. 2005;19:203–8.

    Article  PubMed  CAS  Google Scholar 

  • Nehru B, Bhalla P. Reversal of an aluminium induced alteration in redox status in different regions of rat brain by administration of centrophenoxine. Mol Cell Biochem. 2006;290:185–91.

    Article  PubMed  CAS  Google Scholar 

  • Ohyashiki T, Satoh E, Okada M, Takadera T, Sahara M. Nerve growth factor protects against aluminum-mediated cell death. Toxicology. 2002;176:195–207.

    Article  PubMed  CAS  Google Scholar 

  • Peto MV. Aluminum and iron in humans: bioaccumulation, pathology and removal. Rejuvenation Res. 2010;13:589–98.

    Article  PubMed  CAS  Google Scholar 

  • Petzold GC, Murthy VN. Role of astrocytes in neurovascular coupling. Neuron. 2011;71:782–97.

    Article  PubMed  CAS  Google Scholar 

  • Praticò D, Uryu K, Sung S, Tang S, Trojanowski J. Q. & Lee V. M.-Y. Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice. The FASEB Journal. 2002. 16, 1138–1140

  • Priest ND. The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J Environ Monit. 2004;6:375–403.

    Article  PubMed  CAS  Google Scholar 

  • Reichenbach A, Wolburg H. Structural association of astrocytes with neurons and vasculature: defining territorial boundaries astrocytes in (patho)physiology of the nervous system. In: Haydon PG, Parpura V, editors. New York: Springer; 2009.

  • Richards SA, Muter J, Ritchie P, Lattanzi G, Hutchison CJ. The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine. Hum Mol Genet. 2011;20:3997–4004.

    Article  PubMed  CAS  Google Scholar 

  • Romundstad P, Haldorsen T, Andersen A. Lung and bladder cancer among workers in a Norwegian aluminium reduction plant. Occup Environ Med. 2000;57:495–9.

    Article  PubMed  CAS  Google Scholar 

  • Rondeau V, Commenges D, Jacqmin-Gadda H, Dartigues J-F. Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study. Am J Epidemiol. 2000;152:59–66.

    Article  PubMed  CAS  Google Scholar 

  • Rondeau V, Jacqmin-Gadda H, Commenges D, Helmer C, Dartigues J-F. Aluminum and silica in drinking water and the risk of alzheimer's disease or cognitive decline: findings from 15-year follow-up of the PAQUID Cohort. Am J Epidemiol. 2009;169:489–96.

    Article  PubMed  Google Scholar 

  • Rosenlöf K, Fyhrquist F, Tenhunen R. Erythropoietin, aluminium, and anaemia in patients on haemodialysis. Lancet. 1990;335:247–9.

    Article  PubMed  Google Scholar 

  • Rouault TA, Tong W-H. Iron–sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol. 2005;6:345–51.

    Article  PubMed  CAS  Google Scholar 

  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 2005;7:77–85.

    Article  PubMed  CAS  Google Scholar 

  • Silva VlS, Miguel Cordeiro J, Matos MJ, Oliveira CR, Gonçalves PP. Aluminum accumulation and membrane fluidity alteration in synaptosomes isolated from rat brain cortex following aluminum ingestion: effect of cholesterol. Neurosci Res. 2002;44:181–93.

    Article  PubMed  CAS  Google Scholar 

  • Soni MG, White SM, Flamm WG, Burdock GA. Safety evaluation of dietary aluminum. Regul Toxicol Pharmacol. 2001;33:66–79.

    Article  PubMed  CAS  Google Scholar 

  • Sood P, Nahar U, Nehru B. Curcumin attenuates aluminum-induced oxidative stress and mitochondrial dysfunction in rat brain. Neurotox Res. 2011;20:351–61.

    Article  PubMed  CAS  Google Scholar 

  • Taylor JM, Main BS, Crack PJ. Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson's disease. Neurochem Int. 2013. doi:10.1016/j.neuint.2012.12.016.

  • Tomljenovic L. Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link? J Alzheimers Dis. 2011;23:567–98.

    PubMed  CAS  Google Scholar 

  • Vaz FM, Wanders RJA. Carnitine biosynthesis in mammals. Biochem J. 2002;361:417–29.

    Article  PubMed  CAS  Google Scholar 

  • Wang XF, Cynader MS. Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity. J Neurosci. 2001;21:3322–31.

    PubMed  CAS  Google Scholar 

  • Ward RJ, Zhang Y, Crichton RR. Aluminium toxicity and iron homeostasis. J Inorg Biochem. 2001;87:9–14.

    Article  PubMed  CAS  Google Scholar 

  • Wu Z, Du Y, Xue H, Wu Y, Zhou B. Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production. Neurobiol Aging. 2012;33:199. e1-199.e12.

    PubMed  CAS  Google Scholar 

  • Yokel RA, Hicks CL, Florence RL. Aluminum bioavailability from basic sodium aluminum phosphate, an approved food additive emulsifying agent, incorporated in cheese. Food Chem Toxicol. 2008;46:2261–6.

    Article  PubMed  CAS  Google Scholar 

  • Yousef MI, Salama AF. Propolis protection from reproductive toxicity caused by aluminium chloride in male rats. Food Chem Toxicol. 2009;47:1168–75.

    Article  PubMed  CAS  Google Scholar 

  • Yuan CY, Lee YJ, Hsu GS. Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats. J Biomed Sci. 2012;19:51.

    Article  PubMed  CAS  Google Scholar 

  • Zatta P, Lain E, Cagnolini C. Effects of aluminum on activity of Krebs cycle enzymes and glutamate dehydrogenase in rat brain homogenate. Eur J Biochem. 2000;267:3049–55.

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Banerjee A, Banks WA, Ercal N. N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells. Brain Res. 2009;1275:87–95.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Laurentian University and Industry Canada. Joseph Lemire was a recipient of the Alexander Graham Bell Canadian Graduate Scholarship (NSERC) and currently holds an NSERC-PDF, Christopher Auger is a recipient of the NSERC PGS-D.

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The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

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Han, S., Lemire, J., Appanna, V.P. et al. How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale. Cell Biol Toxicol 29, 75–84 (2013). https://doi.org/10.1007/s10565-013-9239-0

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