Skip to main content
SpringerLink
Log in

Causal effects of synthetic chemicals on mitochondrial deficits and diabetes pandemic

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

A Correction to this article was published on 29 August 2018

Abstract

It is generally accepted that mitochondrial deficits cause many common age-associated diseases including type 2 diabetes. However, it has not been understood what causes mitochondrial damages and how to interrupt the development of the diseases in patients. Recent epidemiologic studies demonstrated a positive correlation between serum concentrations of environmental pollutants and insulin resistance/diabetes. Emerging data strongly suggest that some synthetic pollutants disturb the signaling pathway critical for energy homeostasis and insulin action. The synthetic chemicals are possibly involved in pathogenesis of insulin resistance and diabetes as mitochondria-disturbing agents. In this review, we present a molecular scheme to address the contribution of environmental synthetic chemicals to this metabolic catastrophe. Efforts to identify synthetic chemicals with mitochondria-damaging activities may open a new era to develop effective therapeutic interventions against the worldwide-spreading metabolic disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

T2DM:

Type 2 diabetes

GWAS:

Genome-Wide Association Study

EWAS:

Environmental-Wide Association Study

OR:

Odds ratio

POPs:

Persistent organic pollutants

PCB:

Polychlorinated biphenyl

OC:

Organochlorine

EDC:

Endocrine disrupting chemicals

mtDNA:

Mitochondrial DNA

Ndna:

Nuclear DNA

OXPHOS:

Oxidative phosphorylation

AhR:

Aryl hydrocarbon receptor

AhRR:

AhR repressor

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

ROS:

Reactive oxygen species

FICZ:

6-formylindolo[3,2-b]carbazole

MPP+ :

1-methyl-4-phenylpyridinium

PD:

Parkinson’s disease

CMAPS:

Cell-based mitochondrial activity profiling assays

References

  • Ahn, S.Y., Y.S. Choi, H.J. Koo, J.H. Jeong, W.H. Park, M. Kim, Y. Piao, and Y.K. Pak. 2010. Mitochondrial dysfunction enhances the migration of vascular smooth muscles cells via suppression of Akt phosphorylation. Biochimica et Biophysica Acta 1800: 275–281.

    Article  PubMed  CAS  Google Scholar 

  • Beischlag, T.V., J. Luis Morales, B.D. Hollingshead, and G.H. Perdew. 2008. The aryl hydrocarbon receptor complex and the control of gene expression. Critical Reviews in Eukaryotic Gene Expression 18: 207–250.

    Article  PubMed  CAS  Google Scholar 

  • Beischlag, T.V., S. Wang, D.W. Rose, J. Torchia, S. Reisz-Porszasz, K. Muhammad, W.E. Nelson, M.R. Probst, M.G. Rosenfeld, and O. Hankinson. 2002. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Molecular and Cellular Biology 22: 4319–4333.

    Article  PubMed  CAS  Google Scholar 

  • Camacho, I.A., N. Singh, V.L. Hegde, M. Nagarkatti, and P.S. Nagarkatti. 2005. Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to aryl hydrocarbon receptor-dependent nuclear translocation of NF-kappaB and expression of Fas ligand in thymic stromal cells and consequent apoptosis in T cells. Journal of Immunology 175: 90–103.

    CAS  Google Scholar 

  • Chen, Q., N.N. Huang, J.T. Huang, S. Chen, J. Fan, C. Li, and F.K. Xie. 2009. Sodium benzoate exposure downregulates the expression of tyrosine hydroxylase and dopamine transporter in dopaminergic neurons in developing zebrafish. Birth Defects Research Part B, Developmental and Reproductive Toxicology 86: 85–91.

    Article  PubMed  CAS  Google Scholar 

  • Chen, S.C., T.L. Liao, Y.H. Wei, C.R. Tzeng, and S.H. Kao. 2010. Endocrine disruptor, dioxin (TCDD)-induced mitochondrial dysfunction and apoptosis in human trophoblast-like JAR cells. Molecular Human Reproduction 16: 361–372.

    Article  PubMed  CAS  Google Scholar 

  • Choi, Y.S., J.H. Jeong, H.K. Min, H.J. Jung, D. Hwang, S.W. Lee, and Y.K. Pak. 2011. Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: Identification of mitochondrial histones. Molecular BioSystems 7: 1523–1536.

    Article  PubMed  CAS  Google Scholar 

  • Denison, M.S., A. Pandini, S.R. Nagy, E.P. Baldwin, and L. Bonati. 2002. Ligand binding and activation of the Ah receptor. Chemico-Biological Interactions 141: 3–24.

    Article  PubMed  CAS  Google Scholar 

  • Denison, M.S., A.A. Soshilov, G. He, D.E. Degroot, and B. Zhao. 2011. Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicological Sciences 124: 1–22.

    Article  PubMed  CAS  Google Scholar 

  • Dimauro, S., and E.A. Schon. 2003. Mitochondrial respiratory-chain diseases. New England Journal of Medicine 348: 2656–2668.

    Article  PubMed  CAS  Google Scholar 

  • Evans, B.R., S.I. Karchner, L.L. Allan, R.S. Pollenz, R.L. Tanguay, M.J. Jenny, D.H. Sherr, and M.E. Hahn. 2008. Repression of aryl hydrocarbon receptor (AHR) signaling by AHR repressor: role of DNA binding and competition for AHR nuclear translocator. Molecular Pharmacology 73: 387–398.

    Article  PubMed  CAS  Google Scholar 

  • Forgacs, A.L., L.D. Burgoon, S.G. Lynn, J.J. Lapres, and T. Zacharewski. 2010. Effects of TCDD on the expression of nuclear encoded mitochondrial genes. Toxicology and Applied Pharmacology 246: 58–65.

    Article  PubMed  CAS  Google Scholar 

  • Hong, N.S., K.S. Kim, I.K. Lee, P.M. Lind, L. Lind, D.R. Jacobs, and D.H. Lee. 2012. The association between obesity and mortality in the elderly differs by serum concentrations of persistent organic pollutants: A possible explanation for the obesity paradox. International Journal of Obesity (Lond) 36: 1170–1175.

    Article  CAS  Google Scholar 

  • Jonietz, E. 2012. Pathology: Cause and effect. Nature 485: S10–S11.

    Article  PubMed  CAS  Google Scholar 

  • Kiss, E.A., C. Vonarbourg, S. Kopfmann, E. Hobeika, D. Finke, C. Esser, and A. Diefenbach. 2011. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334: 1561–1565.

    Article  PubMed  CAS  Google Scholar 

  • Lane, N. 2006. Mitochondrial disease: Powerhouse of disease. Nature 440: 600–602.

    Article  PubMed  CAS  Google Scholar 

  • Larsen, N.B., M. Rasmussen, and L.J. Rasmussen. 2005. Nuclear and mitochondrial DNA repair: Similar pathways? Mitochondrion 5: 89–108.

    Article  PubMed  CAS  Google Scholar 

  • Lee, C.S., H.H. Ko, J.H. Song, and E.S. Han. 2002. Effect of R-(−)-deprenyl and harmaline on dopamine- and peroxynitrite-induced membrane permeability transition in brain mitochondria. Neurochemical Research 27: 215–224.

    Article  PubMed  CAS  Google Scholar 

  • Lee, D.H., I.K. Lee, K. Song, M. Steffes, W. Toscano, B.A. Baker, and D.R. Jacobs Jr. 2006. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: Results from the National Health and Examination Survey 1999–2002. Diabetes Care 29: 1638–1644.

    Article  PubMed  CAS  Google Scholar 

  • Lee, D.H., L. Lind, D.R. Jacobs Jr, S. Salihovic, B. Van Bavel, and P.M. Lind. 2012. Associations of persistent organic pollutants with abdominal obesity in the elderly: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Environment International 40: 170–178.

    Article  PubMed  CAS  Google Scholar 

  • Lee, D.H., M.W. Steffes, A. Sjodin, R.S. Jones, L.L. Needham, and D.R. Jacobs Jr. 2011. Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes. PLoS ONE 6: e15977.

    Article  PubMed  CAS  Google Scholar 

  • Li, Y., S. Innocentin, D.R. Withers, N.A. Roberts, A.R. Gallagher, E.F. Grigorieva, C. Wilhelm, and M. Veldhoen. 2011. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147: 629–640.

    Article  PubMed  CAS  Google Scholar 

  • Lim, S., S.Y. Ahn, I.C. Song, M.H. Chung, H.C. Jang, K.S. Park, K.U. Lee, Y.K. Pak, and H.K. Lee. 2009. Chronic exposure to the herbicide, atrazine, causes mitochondrial dysfunction and insulin resistance. PLoS ONE 4: e5186.

    Article  PubMed  Google Scholar 

  • Murphy, M.P., M.J. Krueger, S.O. Sablin, R.R. Ramsay, and T.P. Singer. 1995. Inhibition of complex I by hydrophobic analogues of N-methyl-4-phenylpyridinium (MPP+) and the use of an ion-selective electrode to measure their accumulation by mitochondria and electron-transport particles. The Biochemical Journal 306(Pt 2): 359–365.

    PubMed  CAS  Google Scholar 

  • Neel, B.A., and R.M. Sargis. 2011. The paradox of progress: Environmental disruption of metabolism and the diabetes epidemic. Diabetes 60: 1838–1848.

    Article  PubMed  CAS  Google Scholar 

  • Neri, T., V. Merico, F. Fiordaliso, M. Salio, P. Rebuzzini, L. Sacchi, R. Bellazzi, C.A. Redi, M. Zuccotti, and S. Garagna. 2011. The differentiation of cardiomyocytes from mouse embryonic stem cells is altered by dioxin. Toxicology Letters 202: 226–236.

    Article  PubMed  CAS  Google Scholar 

  • Nicklas, W.J., I. Vyas, and R.E. Heikkila. 1985. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sciences 36: 2503–2508.

    Article  PubMed  CAS  Google Scholar 

  • Opitz, C.A., U.M. Litzenburger, F. Sahm, M. Ott, I. Tritschler, S. Trump, T. Schumacher, L. Jestaedt, D. Schrenk, M. Weller, M. Jugold, G.J. Guillemin, C.L. Miller, C. Lutz, B. Radlwimmer, I. Lehmann, A. Von Deimling, W. Wick, and M. Platten. 2011. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478: 197–203.

    Article  PubMed  CAS  Google Scholar 

  • Pak, Y.K., and J.H. Jeong. 2010. Mitochondria: The secret chamber of therapeutic targets for age-associated degenerative diseases. Biomolecules & Therapeutics 18: 235–245.

    Article  CAS  Google Scholar 

  • Patel, C.J., J. Bhattacharya, and A.J. Butte. 2010. An Environment-Wide Association Study (EWAS) on type 2 diabetes mellitus. PLoS ONE 5: e10746.

    Article  PubMed  Google Scholar 

  • Piao, Y., H.G. Kim, M.S. Oh, and Y.K. Pak. 2012. Overexpression of TFAM, NRF-1 and myr-AKT protects the MPP(+)-induced mitochondrial dysfunctions in neuronal cells. Biochimica et Biophysica Acta 1820: 577–585.

    Article  PubMed  CAS  Google Scholar 

  • Piper, P.W. 1999. Yeast superoxide dismutase mutants reveal a pro-oxidant action of weak organic acid food preservatives. Free Radical Biology & Medicine 27: 1219–1227.

    Article  CAS  Google Scholar 

  • Ruzzin, J., R. Petersen, E. Meugnier, L. Madsen, E.J. Lock, H. Lillefosse, T. Ma, S. Pesenti, S.B. Sonne, T.T. Marstrand, M.K. Malde, Z.Y. Du, C. Chavey, L. Fajas, A.K. Lundebye, C.L. Brand, H. Vidal, K. Kristiansen, and L. Froyland. 2010. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environmental Health Perspectives 118: 465–471.

    Article  PubMed  CAS  Google Scholar 

  • Sarioglu, H., S. Brandner, M. Haberger, C. Jacobsen, J. Lichtmannegger, M. Wormke, and U. Andrae. 2008. Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced proteome changes in 5L rat hepatoma cells reveals novel targets of dioxin action including the mitochondrial apoptosis regulator VDAC2. Molecular and Cellular Proteomics 7: 394–410.

    Article  PubMed  CAS  Google Scholar 

  • Schlezinger, J.J., P.L. Bernard, A. Haas, P. Grandjean, P. Weihe, and D.H. Sherr. 2010. Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans. Environmental Health Perspectives 118: 693–698.

    Article  PubMed  CAS  Google Scholar 

  • Senft, A.P., T.P. Dalton, D.W. Nebert, M.B. Genter, A. Puga, R.J. Hutchinson, J.K. Kerzee, S. Uno, and H.G. Shertzer. 2002. Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radical Biology and Medicine 33: 1268–1278.

    Article  PubMed  CAS  Google Scholar 

  • Shen, D., T.P. Dalton, D.W. Nebert, and H.G. Shertzer. 2005. Glutathione redox state regulates mitochondrial reactive oxygen production. Journal of Biological Chemistry 280: 25305–25312.

    Article  PubMed  CAS  Google Scholar 

  • Shetty, P.V., B.Y. Bhagwat, and W.K. Chan. 2003. P23 enhances the formation of the aryl hydrocarbon receptor–DNA complex. Biochemical Pharmacology 65: 941–948.

    Article  PubMed  CAS  Google Scholar 

  • Storch, A., Y.I. Hwang, D.A. Gearhart, J.W. Beach, E.J. Neafsey, M.A. Collins, and J. Schwarz. 2004. Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson’s disease: Relationship to transporter-dependent uptake. Journal of Neurochemistry 89: 685–694.

    Article  PubMed  CAS  Google Scholar 

  • Tanaka, T., A. Morita, M. Kato, T. Hirai, T. Mizoue, Y. Terauchi, S. Watanabe, and M. Noda. 2011. Congener-specific polychlorinated biphenyls and the prevalence of diabetes in the Saku Control Obesity Program (SCOP). Endocrine Journal 58: 589–596.

    Article  PubMed  CAS  Google Scholar 

  • Tappenden, D.M., S.G. Lynn, R.B. Crawford, K. Lee, A. Vengellur, N.E. Kaminski, R.S. Thomas, and J.J. Lapres. 2011. The aryl hydrocarbon receptor interacts with ATP5alpha1, a subunit of the ATP synthase complex, and modulates mitochondrial function. Toxicology and Applied Pharmacology 254: 299–310.

    Article  PubMed  CAS  Google Scholar 

  • Tariq, M., M. Arshaduddin, N. Biary, K. Al Moutaery, and S. Al Deeb. 2002. 2-Deoxy-d-glucose attenuates harmaline induced tremors in rats. Brain Research 945: 212–218.

    Article  PubMed  CAS  Google Scholar 

  • Tian, Y., A.B. Rabson, and M.A. Gallo. 2002. Ah receptor and NF-kappaB interactions: Mechanisms and physiological implications. Chemico-Biological Interactions 141: 97–115.

    Article  PubMed  CAS  Google Scholar 

  • Tsay, H.J., Y.H. Wang, W.L. Chen, M.Y. Huang, and Y.H. Chen. 2007. Treatment with sodium benzoate leads to malformation of zebrafish larvae. Neurotoxicology and Teratology 29: 562–569.

    Article  PubMed  CAS  Google Scholar 

  • Wagner, B.K., T.J. Gilbert, J. Hanai, S. Imamura, N.E. Bodycombe, R.S. Bon, H. Waldmann, P.A. Clemons, V.P. Sukhatme, and V.K. Mootha. 2011. A small-molecule screening strategy to identify suppressors of statin myopathy. ACS Chemical Biology 6: 900–904.

    Article  PubMed  CAS  Google Scholar 

  • Wagner, B.K., T. Kitami, T.J. Gilbert, D. Peck, A. Ramanathan, S.L. Schreiber, T.R. Golub, and V.K. Mootha. 2008. Large-scale chemical dissection of mitochondrial function. Nature Biotechnology 26: 343–351.

    Article  PubMed  CAS  Google Scholar 

  • Wild, S., G. Roglic, A. Green, R. Sicree, and H. King. 2004. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053.

    Article  PubMed  Google Scholar 

  • Wincent, E., J. Bengtsson, A. Mohammadi Bardbori, T. Alsberg, S. Luecke, U. Rannug, and A. Rannug. 2012. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences of the Unites States of America 109: 4479–4484.

    Article  CAS  Google Scholar 

  • Zudaire, E., N. Cuesta, V. Murty, K. Woodson, L. Adams, N. Gonzalez, A. Martinez, G. Narayan, I. Kirsch, W. Franklin, F. Hirsch, M. Birrer, and F. Cuttitta. 2008. The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. Journal of Clinical Investigation 118: 640–650.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by NRF grant funded by the Korean Ministry of Education, Science, and Technology (20120001162) and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare (B12002912010000100). The funding source was not involved in study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication.

Author information

Author notes

  1. Youngmi Kim Pak

    Present address: , #26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Korea

Authors and Affiliations

  1. Department of Physiology, College of Medicine, Kyung Hee University, Seoul, 130-701, Korea

    Wook-Ha Park, Young-Chul Kang, Ying Piao, Daniel Hyungseok Pak & Youngmi Kim Pak

  2. Department of Neuroscience, College of Medicine, Kyung Hee University, Seoul, 130-701, Korea

    Wook-Ha Park, Young-Chul Kang, Ying Piao, Daniel Hyungseok Pak & Youngmi Kim Pak

  3. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Daniel Hyungseok Pak

Authors
  1. Wook-Ha Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-Chul Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Hyungseok Pak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youngmi Kim Pak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Youngmi Kim Pak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, WH., Kang, YC., Piao, Y. et al. Causal effects of synthetic chemicals on mitochondrial deficits and diabetes pandemic. Arch. Pharm. Res. 36, 178–188 (2013). https://doi.org/10.1007/s12272-013-0022-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-013-0022-9

Keywords

Search

Navigation