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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

  • Frank JordanEmail author
  • Natalia NemeriaEmail author
  • Gary Gerfen
Original Paper

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.

Keywords

2-Oxoglutarate and 2-oxoadipate dehydrogenase complexes Thiamin diphosphate-enamine radical Hydrogen peroxide Oxidative stress 

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.

Notes

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).

Compliance with Ethical Standards

Conflict of interest

The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. 1.Department of ChemistryRutgers UniversityNewarkUSA
  2. 2.Department of Physiology and BiophysicsAlbert Einstein College of MedicineBronxUSA

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