Skip to main content

Advertisement

SpringerLink
Log in

Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Both Generate Superoxide/H2O2 in a Side Reaction and Each Could Contribute to Oxidative Stress in Mitochondria

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

According to recent findings, the human 2-oxoglutarate dehydrogenase complex (hOGDHc) could be an important source of the reactive oxygen species in the mitochondria and could contribute to mitochondrial abnormalities associated with multiple neurodegenerative diseases, including Alzheimer’s disease, Huntington disease, and Parkinson’s disease. The human 2-oxoadipate dehydrogenase (hE1a) is a novel protein, which is encoded by the DHTKD1 gene. Both missence and nonsense mutations were identified in the DHTKD1 that lead to alpha-aminoadipic and alpha-oxoadipic aciduria, a metabolic disorder with a wide variety of the neurological abnormalities, and Charcot-Marie-Tooth disease type 2Q, an inherited neurological disorder affecting the peripheral nervous system. Recently, the rare pathogenic mutations in DHTKD1 and an increased H2O2 production were linked to the genetic ethiology of Eosinophilic Esophagitis (EoE), a chronic allergic inflammatory esophageal disorder. In view of the importance of hOGDHc in the tricarboxylic acid cycle (TCA cycle) and hE1a on the l-lysine, l-hydroxylysine and l-tryptophan degradation pathway in mitochondria, and to enhance our current understanding of the mechanism of superoxide/H2O2 generation by hOGDHc, and by human 2-oxoadipate dehydrogenase complex (hOADHc), this review focuses on several novel and unanticipated recent findings in vitro that emerged from the Jordan group’s research. Most significantly, the hE1o and hE1a now join the hE3 as being able to generate the superoxide/H2O2 in mitochondria.

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

Scheme 1
Scheme 2
Fig. 1
Scheme 3
Fig. 2
Scheme 4
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

hOGDHc:

Human 2-oxoglutarate dehydrogenase complex

hE1o:

2-Oxoglutarate dehydrogenase, the first E1 component of hOGDHc;

hE2o:

Dihydrolipoyl succinyltransferase, the second E2 component of hOGDHc

hE3:

Dihydrolipoyl dehydrogenase, the third E3 component of all 2-oxoacid dehydrogenase complexes

hOADHc:

human 2-oxoadipate dehydrogenase complex, assembled from hE1a + hE2o + hE3

hE1a:

2-Oxoadipate dehydrogenase, the first component of hOADHc

DHTKD1 :

Gene coding hE1a

TCA cycle:

Tricarboxylic acid cycle

H2O2 :

Hydrogen peroxide

ROS:

Reactive oxygen species

ThDP:

Thiamin diphosphate

OG:

2-Oxoglutarate

OA:

2-Oxoadipate

DCPIP:

2,6-Dichlorophenol-indophenol

EPR:

Electron Paramagnetic Resonance.

References

  1. Nemeria NS, Chakraborty S, Baykal A, Korotchkina LG, Patel MS, Jordan F (2007) The 1′,4′-iminopyrimidine tautomer of thiamin diphosphate is poised for catalysis in asymmetric active centers on enzymes. Proc Natl Acad Sci USA 104:78–82

    Article  CAS  PubMed  Google Scholar 

  2. Nemeria NS, Chakraborty S, Balakrishnan A, Jordan F (2009) Reaction mechanisms of thiamin diphosphate enzymes:defining states of ionization and tautomerization of the cofactor at individual steps. FEBS J 276:2432–2446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Balakrishnan A, Gao Y, Moorjani P, Nemeria NS, Tittmann K, Jordan F (2012) Bifunctionality of the thiamin diphosphate cofactor: assignment of tautomeric/ionization states of the 4′-aminopyrimidine ring when various intermdediates occupy the active sites during the catalysis of yeast pyruvate decarboxylase. J Am Chem Soc 134:3873–3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Patel H, Nemeria NS, Brammer LA, Freel Meyers CL, Jordan F (2012) Observation of thiamin-bound intermediates and microscopic rate constants for their interconversion on 1-deoxy-d-xylulose 5-phosphate synthase: 600-fold rate acceleration of pyruvate decarboxylation by D-glyceraldehyde-3-phosphate. J Am Chem Soc 134:18374–18379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nemeria N, Binshtein E, Patel H, Balakrishnan A, Vered I, Shaanan B, Barak Z, Chipman D, Jordan F (2012) Glyoxylate carboligase: a unique thiamin diphosphate-dependent enzyme that can cycle between the 4′-aminopyrymidinium and 1′4′-iminopyrimidine tautomeric forms in the absence of the conserved glutamate. Biochemistry 51:7940–7952

    Article  CAS  PubMed  Google Scholar 

  6. Jordan F, Patel H (2013) Catalysis in enzymatic decarboxylations: comparison of selected cofactor-dependent and cofactor-independent examples. ACS Catal 3:1601–1617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Balakrishnan A, Jordan F, Nathan CF (2013) Influence of allosteric regulators on individual steps in the reaction catalyzed by Micobacterium tuberculosis 2-hydroxy-3-oxoadipate synthase. J Biol Chem 288:21688–21702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jordan F, Nemeria NS (2014) Progress in the experimental observation of thiamin diphosphate-bound intermediates on enzymes and mechanistic information derived from these observations. Bioorg Chem 57:251–262

    Article  CAS  PubMed  Google Scholar 

  9. Nemeria NS, Ambrus A, Patel H, Gerfen G, Adam-Vizi V, Tretter L, Zhou J, Wang J, Jordan F (2014) Human 2-oxoglutarate dehydrogenase complex E1 component forms a thiamin-derived radical by aerobic oxidation of the enamine intermediate. J Biol Chem 289:29859–29873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nemeria NS, Gerfen G, Guevara E, Nareddy PR, Szostak M, Jordan F (2017) The human Krebs cycle 2-oxoglutarate dehydrogenase complex creates an additional source of superoxide/hydrogen peroxide from 2-oxoadipate as an alternative substrate. Free Radic Biol Med 108:644–654

    Article  CAS  PubMed  Google Scholar 

  11. Zhou J, Yang L, Ozohanics O, Zhang X, Wang J, Ambrus A, Arjunan P, Brukh R, Nemeria NS, Furey W, Jordan F (2018) A multipronged approach unravels unprecedented protein- protein interactions in the human 2-oxoglutarate dehydrogenase multienzyme complex. J Biol Chem 293:19213–19227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nemeria NS, Gerfen G, Yang L, Zhang X, Jordan F (2018) Evidence for functional and regulatory cross-talk between the tricarboxylic acid cycle 2-oxoglutarate dehydrogenase complex and 2-oxoadipate dehydrogenase on the l-lysine, l-hydroxylysine and l-tryptophan degradation pathways from studies in vitro. Biochim Biophys Acta 1859:932–939. https://doi.org/10.1016/j.bbabio.2018.05.001

    Article  CAS  Google Scholar 

  13. Nemeria NS, Gerfen G, Reddy Nareddy P, Yang L, Zhang X, Szostak M, Jordan F (2018) The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species. Free Radic Biol Chem 115:136–145

    Article  CAS  Google Scholar 

  14. Chen H, Denton TT, Xu H, Calingasan N, Beal MF, Gibson GE (2016) Reductions in the mitochondrial enzyme α-ketoglutarate dehydrogenase complex in neurodegenerative disease-beneficial or detrimental? J Neurochem 139:823–839. https://doi.org/10.1111/jnc.13836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bunik VI, Sievers C (2002) Inactivation of the 2-oxo acid dehydrogenase complexes upon generation of intrinsic radical species. Eur J Biochem 269:5004–5015

    Article  CAS  PubMed  Google Scholar 

  16. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tretter L, Adam-Vizi V (2004) Generation of reactive oxygen species in the reaction catalyzed by α-ketoglutarate dehydrogenase. J Neurosci 24:7771–7778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tretter L, Adam-Vizi V (2005) Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci 360:2335–2345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zündorf G, Kahlert S, Bunik VI, Reiser G (2009) α-Ketoglutarate dehydrogenase contributes to production of reactive oxygen species in glutamate-stimulated hippocampal neurons in situ. Neuroscience 158:610–616

    Article  PubMed  Google Scholar 

  20. Quinlan CL, Goncalves RLS, Hey-Mogensen M, Yadava N, Bunik VI, Brand M (2014) The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. J Biol Chem 289:8312–8325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brand MD (2016) Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Rad Biol Med 100:14–31

    Article  CAS  PubMed  Google Scholar 

  22. Danhauser K, Sauer SW, Haack TB, Wieland T, Staufner C, Graf E et al (2012) DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. Am J Hum Genet 91:1082–1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hagen J, Brinke H, Wanders RJA, Knegt AC, Oussoren E, Hoogeboom JM, Ruijter GJG, Becker D, Schwab KO, Franke I, Duran M, Waterham HR, Sass JO, Houten SM (2015) Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis 38:873–879

    Article  CAS  PubMed  Google Scholar 

  24. Stiles AR, Venturoni L, Mucci G, Elbalalesy N, Woontner M, Goodmann S, Abdenur JE (2015) New cases of DHTKD1 mutations in patients with 2-ketoadipic aciduria. JIMD Reports 25:15–19

    Article  PubMed  PubMed Central  Google Scholar 

  25. Xu WY, Gu MM, Sun LH, Guo WT, Zhu HB, Ma JF, Yuan WT, Kuang Y, Ji BJ, Wu XL, Chen Y, Zhang HX, Sun FT, Huang W, Huang L, Chen SD, Wang ZG (2012) A nonsence mutation in DHTKD1 causes Charcot-Marie-Tooth type 2 in a large chinese pedigree. Am J Hum Genet 91:1088–1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu W, Zhu H, Gu M, Luo Q, Ding J, Yao Y, Chen F, Wang Z (2013) DHTKD1 is essential for mitochondrial biogenesis and function maintenance. FEBS Lett 587:3587–3592

    Article  CAS  PubMed  Google Scholar 

  27. Baets J, De Jonghe P, TimmermanV (2014) Recent advances in Charcot-Marie-Tooth disease. Curr Opin Neurol 27:532–540

    Article  CAS  PubMed  Google Scholar 

  28. Xu WY, Zhu H, Shen Y, Wan YH, Tu XD, Wu WT, Tang L, Zhang HX, Lu SY, Jin XL, Fei J, Wang ZG (2018) DHTKD1 deficiency causes Charcot-Marie-Tooth disease in mice. Mol Cell Biol 38:e00085–e00018. https://doi.org/10.1128/MCB.00085-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sherrill JD, Kc K, Wang X, Wen T, Chamberlin A, Stucke EM, Collins MH, Abonia JP, Peng Y, Wu Q, Putnam PE, Dexheimer PJ, Aronow BJ, Kottyan LC, Kaufman KM, Harley JB, Huang T, Rothenberg ME (2018) Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHc as linkers between mitochondrial disfynction and eosinophilic esophagitis. JCI Insight 3:1–20. https://doi.org/10.1172/jci.insight.99922

    Article  Google Scholar 

  30. Biagosch C, Ediga RD, Hensler SV, Faerberboeck M, Kuehn R, Wurst W, Meitinger T, Kölker S, Sauer S, Prokisch H (2017) Elevated glutaric acid levels in Dhtkd1-/Gcdh-double knockout mice challenge our current understanding of lysine metabolism. Biochim Biophys Acta - Molecular Basis of Disease 1863:2220–2228

    Article  CAS  PubMed  Google Scholar 

  31. Schmiesing J, Lohmöller B, Schweizer M, Tidov H, Gersting SW, Muntau AG, Braulke T, Mühlhausen G (2017) Disease-causing mutations affecting surface residues of mitochondrial glutaryl-CoA dehydrogenase impair stability, heteromeric complex formation and mitochondria architecture. Hum Mol Genet 26:538–551

    CAS  PubMed  Google Scholar 

  32. Goodman SI, Frerman FE (2001) Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, pp 2195–2204

  33. Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, Park J, Chen Y, Huang H, Zhang Y et al (2014)Lysine glutarylation is a protein pasttranslational modification regulated by SIRT5. Cell Metab 19:605–617

  34. Schmiesing J, Storch S, Dörfler AC, Schweizer M, Makrypidi-Fraune G, Thelen M, Sylvester M, Gieselmann V, Meyer-Schwesinger C, Koch-Nolte F, Tidow H, Mühlhausen C, Waheed A, Sly WS, Braulke T (2018) Disease-linked glutarylation impairs function and interactions of mitochondrial proteins and contributes to mitochondrial heterogeneity. Cell Rep 24:2946–2956. http://creativecommons.org/licenses/by-nc-nd/4.0/

  35. Reed LJ (2001) A trial of research from lipoic acid to α-keto acid dehydrogenase complexes. J Biol Chem 276:38329–38336

    Article  CAS  PubMed  Google Scholar 

  36. Perham RN (1991) Domains, motifs, and linkers in 2-oxo acid dehydrogenase multienzyme complexes: a paradigm in the design of a multifunctional protein. Biochemistry 30:8501–8512

    Article  CAS  PubMed  Google Scholar 

  37. Perham RN (2000) Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu Rev Biochem 69:961–1004

    Article  CAS  PubMed  Google Scholar 

  38. Yeaman SJ (1989) The 2-oxo acid dehydrogenase complexes: recent advances. Biochem J 257:625–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maas E, Bisswanger H (1990) Localization of the alpha-oxoacid dehydrogenase multienzyme complexes within the mitochondrion. FEBS Lett 277:189–190

    Article  CAS  PubMed  Google Scholar 

  40. Bunik VI, Tylicki A, Lukashev NY (2013) Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug designand disease models. FEBS J 280:6412–6442

    Article  CAS  PubMed  Google Scholar 

  41. Frank RAW, Kay CWM, Hirst J, Luisi BF (2008) Off-Pathway, oxigen-dependent thiamine radical in krebs cycle. J Am Chem Soc 130:1662–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mansoorabadi SO, Seravalli J, Furdui C, Krymov V, Gerfen GJ, Begley TP, Melnick J, Ragsdale SW, Reed GH et al (2006) EPR spectroscopic and computational characterization of the hydroxyethylidene-thiamine pyrophosphate radical intermediate of pyruvate: ferredoxin oxidoreductase. Biochemistry 45:7122–7131

    Article  CAS  PubMed  Google Scholar 

  43. Ambrus A, Nemeria NS, Torocsik B, Tretter L, Nilsson M, Jordan F, Adam-Vizi V (2015) Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components. Free Radic Biol Med 89:642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Quinlan CL, Perevoschikova IV, Goncalves RL, Hey-Mogensen M, Brand MD (2013) The determination and analysis of site-specific rates of mitochondrial reactive oxygen species production. Methods Enzymol 526:189–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goncalves RLS, Bunik VI, Brand MD (2016) Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex. Free Radic Biol Med 91:247–255

    Article  CAS  PubMed  Google Scholar 

  46. Bunik VI, Brand MD (2018) Generation of superoxide and hydrogen peroxide by side reactions of mitochondrial 2-oxoacid dehydrogenase complexes in isolation and in cells. Biol Chem 399:407–420

    Article  CAS  PubMed  Google Scholar 

  47. Hoffmann GF, Zschocke J (1999) Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis 22:381–389

    Article  CAS  PubMed  Google Scholar 

  48. Gibson GE, Xu H, Chen HL, Chen W, Denton T, Zhang S (2015) Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines. J Neurochem 134:86–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pan K, Jordan F (1998) DL-S-Methyllipoic acid methyl ester, a kinetically viable model for S-protonated lipoic acid as the oxidizing agent in reductive acyl transfers catalyzed by the 2-oxoacid dehydrogenase multienzyme complex. Biochemistry 37:1357–1364

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported, in whole or in part, by National Institutes of Health [Grant # 9R15GM116077-01 (to F.J.)]; the National Science Foundation [Grant CHE-1402675 (to F.J.) and Grant CHE 1213550 (to G.J.G)]; the Rutgers-Newark Chancellor’s SEED Grant (to F.J).

Author information

Authors and Affiliations

  1. Department of Chemistry, Rutgers University, 73 Warren St, Newark, NJ, 07102-1811, USA

    Frank Jordan & Natalia Nemeria

  2. Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10641-2304, USA

    Gary Gerfen

Authors
  1. Frank Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Nemeria
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary Gerfen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Frank Jordan or Natalia Nemeria.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jordan, F., Nemeria, N. & Gerfen, G. Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Both Generate Superoxide/H2O2 in a Side Reaction and Each Could Contribute to Oxidative Stress in Mitochondria. Neurochem Res 44, 2325–2335 (2019). https://doi.org/10.1007/s11064-019-02765-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-019-02765-w

Keywords

Search

Navigation