← Back to Search
Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species
A. Starkov, G. Fiskum, C. Chinopoulos, Beverl J. Lorenzo, S. Browne, Mulchand S Patel, M. Beal
Published 2004 · Biology
Save to my Library
Download via 🐼 PaperPanda Download via oaDOI Download via OAB Download via LibKey Download via Google Google ScholarAnalyze on Scholarcy Visualize in Litmaps
Reduce the time it takes to create your bibliography by a factor of 10 by using the world’s favourite reference manager
Time to take this seriously.
Mitochondria-produced reactive oxygen species (ROS) are thought to contribute to cell death caused by a multitude of pathological conditions. The molecular sites of mitochondrial ROS production are not well established but are generally thought to be located in complex I and complex III of the electron transport chain. We measured H2O2 production, respiration, and NADPH reduction level in rat brain mitochondria oxidizing a variety of respiratory substrates. Under conditions of maximum respiration induced with either ADP or carbonyl cyanide p-trifluoromethoxyphenylhydrazone,α-ketoglutarate supported the highest rate of H2O2 production. In the absence of ADP or in the presence of rotenone, H2O2 production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of α-ketoglutarate. Isolated mitochondrial α-ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H2O2. NAD+ inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H2O2 production by brain mitochondria isolated from heterozygous knock-out mice deficient in dihydrolipoyl dehydrogenase (Dld). Although this enzyme is a part of both KGDHC and PDHC, there was greater impairment of KGDHC activity in Dld-deficient mitochondria. These mitochondria also produced significantly less H2O2 than mitochondria isolated from their littermate wild-type mice. The data strongly indicate that KGDHC is a primary site of ROS production in normally functioning mitochondria.
This paper references
Limitations of the Phenazine Methosulphate Assay for Succinic and Related Dehydrogenases
O. Arrigoni (1962)
The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen.
A. Boveris (1973)
Enzyme-catalyzed free radical reactions with nicotinamide-adenine nucleotides: I. Lactate dehydrogenase-catalyzed chain oxidation of bound NADH by superoxide radicals
B. H. Bielski (1973)
Oxygen radicals and hydrogen peroxide in rat brain mitochondria
M.Catia Sorgato (1974)
Properties and subunit composition of the pig heart 2-oxoglutarate dehydrogenase.
K. Koike (1974)
Enzyme-catalyzed free radical reactions with nicotinamide adenine nucleotides. II. Lactate dehydrogenase-catalyzed oxidation of reduced nicotinamide adenine dinucleotide by superoxide radicals generated by xanthine oxidase.
P. Chan (1974)
The use of acetylated ferricytochrome c for the detection of superoxide radicals produced in biological membranes.
A. Azzi (1975)
A kinetic study of the alpha-keto acid dehydrogenase complexes from pig heart mitochondria.
M. Hamada (1975)
Ion Pair Formation in Pig Heart Lipoamide Dehydrogenase
R. Matthews (1977)
Studies on the mechanism and kinetics of the 2-oxoglutarate dehydrogenase system from pig heart.
C. L. McMinn (1977)
Effect of ammonia on mitochondrial and cytosolic NADH and NADPH systems in isolated rat liver cells
M. Tischler (1977)
Glyceraldehyde-3-phosphate dehydrogenase-catalyzed chain oxidation of reduced nicotinamide adenine dinucleotide by perhydroxyl radicals.
P. C. Chan (1980)
Magnetic circular dichroism studies on the active-site flavin of lipoamide dehydrogenase.
Templeton Dm (1980)
alpha-Ketoglutarate dehydrogenase complex may be heterogeneous in quaternary structure.
T. Wagenknecht (1983)
Ammonia formation in isolated rat liver mitochondria.
K. Lanoue (1983)
Complex I binds several mitochondrial NAD-coupled dehydrogenases.
B. Sumegi (1984)
Contribution of different enzymes to flavoprotein fluorescence of isolated rat liver mitochondria.
W. Kunz (1985)
Generation of H2O2 in Brain Mitochondria
M. S. Patole (1986)
Cerebral Ischemia and Reperfusion: Prevention of Brain Mitochondrial Injury by Lidoflazine
R. Rosenthal (1987)
Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease.
G. Gibson (1988)
Supramolecular organization of tricarboxylic acid cycle enzymes.
A. E. Lyubarev (1989)
Generation of hydrogen peroxide by brain mitochondria: the effect of reoxygenation following postdecapitative ischemia.
M. Cino (1989)
Regulation of citric acid cycle by calcium.
B. Wan (1989)
Structure-function relationships in dihydrolipoamide acyltransferases.
L. Reed (1990)
Molecular biology and biochemistry of pyruvate dehydrogenase complexes 1
M. Patel (1990)
Kinetic characterization of the pyruvate and oxoglutarate dehydrogenase complexes from human heart.
Y. V. Kiselevsky (1990)
Rapid Isolation of Metabolically Active Mitochondria from Rat Brain and Subregions Using Percoll Density Gradient Centrifugation
N. Sims (1990)
Localization of the α‐oxoacid dehydrogenase multienzyme complexes within the mitochondrion
E. Maas (1990)
Localization of the alpha-oxoacid dehydrogenase multienzyme complexes within the mitochondrion.
E. Maas (1990)
Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+.
R. Ramsay (1992)
Quantification of the content of fluorescent flavoproteins in mitochondria from liver, kidney cortex, skeletal muscle, and brain.
W. Kunz (1993)
Distribution of the α‐ketoglutarate dehydrogenase complex in rat brain
N. Calingasan (1994)
Isolated Cerebral and Cerebellar Mitochondria Produce Free Radicals when Exposed to Elevated Ca2+ and Na+: Implications for Neurodegeneration
J. Dykens (1994)
Activation of molecular oxygen by flavins and flavoproteins.
V. Massey (1994)
Ca(2+)-induced mitochondrial membrane permeabilization: role of coenzyme Q redox state.
A. Kowaltowski (1995)
Transient and steady-state kinetics of the oxidation of scopoletin by horseradish peroxidase compounds I, II and III in the presence of NADH.
L. Marquez (1995)
Opening of the mitochondrial permeability transition pore by uncoupling or inorganic phosphate in the presence of Ca2+ is dependent on mitochondrial‐generated reactive oxygen species
A. Kowaltowski (1996)
Dependence of H2O2 Formation by Rat Heart Mitochondria on Substrate Availability and Donor Age
R. Hansford (1997)
High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria
S. S. Korshunov (1997)
A stable nonfluorescent derivative of resorufin for the fluorometric determination of trace hydrogen peroxide: applications in detecting the activity of phagocyte NADPH oxidase and other oxidases.
M. Zhou (1997)
Mitochondrial Ubiquinone Homologues, Superoxide Radical Generation, and Longevity in Different Mammalian Species*
A. Lass (1997)
Superoxide Production by the Mitochondrial Respiratory Chain
J. Turrens (1997)
Targeted disruption of the murine dihydrolipoamide dehydrogenase gene (Dld) results in perigastrulation lethality.
M. Johnson (1997)
Dependence of H2O2
RG Hansford (1997)
Interaction of α‐Phenyl‐N‐tert‐Butyl Nitrone and Alternative Electron Acceptors with Complex I Indicates a Substrate Reduction Site Upstream from the Rotenone Binding Site
K. Hensley (1998)
Generation of Superoxide Anion by Succinate-Cytochromec Reductase from Bovine Heart Mitochondria*
Li Zhang (1998)
Ca2+-stimulated mitochondrial reactive oxygen species generation and permeability transition are inhibited by dibucaine or Mg2+.
A. Kowaltowski (1998)
The antioxidant defences of brain mitochondria during short-term forebrain ischemia and recirculation in the rat.
N. Sims (1998)
The Thiol-specific Antioxidant Enzyme Prevents Mitochondrial Permeability Transition
Alicia J. Kowaltowski (1998)
Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria.
L. Kwong (1998)
Mitochondrial Oxygen Radical Generation and Leak: Sites of Production in States 4 and 3, Organ Specificity, and Relation to Aging and Longevity
G. Barja (1999)
The alpha-ketoglutarate dehydrogenase complex.
K. F. Sheu (1999)
Mitochondria in Neurodegeneration: Bioenergetic Function in Cell Life and Death
A. Murphy (1999)
Mitochondria in Neurodegeneration: Acute Ischemia and Chronic Neurodegenerative Diseases
G. Fiskum (1999)
The α‐Ketoglutarate Dehydrogenase Complex
KWAN‐FU REX SHEU (1999)
Comparisons of coenzyme Q bound to mitochondrial membrane proteins among different mammalian species.
A. Lass (1999)
Coulometric array HPLC analysis of lipid - soluble vitamins and antioxidants
PH Gamache (1999)
Quantitative α-Ketoglutarate Dehydrogenase Activity Staining in Brain Sections and in Cultured Cells
L. Park (2000)
Effect of coenzyme Q(10) and alpha-tocopherol content of mitochondria on the production of superoxide anion radicals.
A. Lass (2000)
Mitochondria and neuronal survival.
D. Nicholls (2000)
Mitochondrial participation in ischemic and traumatic neural cell death.
G. Fiskum (2000)
Quantitative alpha-ketoglutarate dehydrogenase activity staining in brain sections and in cultured cells.
L. Park (2000)
Effect of coenzyme Q10 and α‐tocopherol content of mitochondria on the production of superoxide anion radicals
A. Lass (2000)
Inhibition of Krebs Cycle Enzymes by Hydrogen Peroxide: A Key Role of α-Ketoglutarate Dehydrogenase in Limiting NADH Production under Oxidative Stress
L. Tretter (2000)
Localization of the Site of Oxygen Radical Generation inside the Complex I of Heart and Nonsynaptic Brain Mammalian Mitochondria
A. Herrero (2000)
Myxothiazol Induces H2O2 Production from Mitochondrial Respiratory Chain
A. Starkov (2001)
DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria.
T. Votyakova (2001)
Opening of the Mitochondrial Permeability Transition Pore Causes Depletion of Mitochondrial and Cytosolic NAD+and Is a Causative Event in the Death of Myocytes in Postischemic Reperfusion of the Heart*
F. Di Lisa (2001)
ΔΨm‐Dependent and ‐independent production of reactive oxygen species by rat brain mitochondria
T. Votyakova (2001)
The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology
Giorgio Lenaz (2001)
Myxothiazol induces H(2)O(2) production from mitochondrial respiratory chain.
A. Starkov (2001)
Inactivation of the 2-oxo acid dehydrogenase complexes upon generation of intrinsic radical species.
V. Bunik (2002)
Generation of reactive oxygen species by the mitochondrial electron transport chain
Y. Liu (2002)
Regulation of hydrogen peroxide production by brain mitochondria by calcium and Bax
A. Starkov (2002)
Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state.
Y. Kushnareva (2002)
Selective inactivation of redox-sensitive mitochondrial enzymes during cardiac reperfusion.
H. Sadek (2002)
Oxidative stress increases internal calcium stores and reduces a key mitochondrial enzyme.
G. Gibson (2002)
Generation of reactive oxygen species by brain mitochondria mediated by alpha-ketoglutarate dehydrogenase
A Starkov (2002)
In situ assay of the intramitochondrial enzymes: use of alamethicin for permeabilization of mitochondria.
Irina S Gostimskaya (2003)
2-Oxo acid dehydrogenase complexes in redox regulation.
V. Bunik (2003)
Truncated product of the bifunctional DLST gene involved in biogenesis of the respiratory chain
T. Kanamori (2003)
Cyclosporin A-insensitive Permeability Transition in Brain Mitochondria
C. Chinopoulos (2003)
Production of Reactive Oxygen Species by Mitochondria
Qun Chen (2003)
Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals
I. Sipos (2003)
Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state
A. Starkov (2003)
Production of reactive oxygen species by mitochondria: central role of complex III
Q Chen (2003)
Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase
L. Tretter (2004)
This paper is referenced by
The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling
K. R. Bhattarai (2021)
Redox signaling in heart failure and therapeutic implications.
D. Weissman (2021)
Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer's disease
Waqar Ahmad (2021)
An IDH1-vitamin C crosstalk drives human erythroid development by inhibiting pro-oxidant mitochondrial metabolism.
Pedro Gonzalez-Menendez (2021)
Climate change affects seed aging? Initiation mechanism and consequences of loss of forest tree seed viability
Joanna Kijowska-Oberc (2021)
Cellular and Mitochondrial Calcium Communication in Obstructive Lung Disorders.
Shakti Sagar (2021)
Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes
N. Nemeria (2021)
Metabolic Reprogramming and Reactive Oxygen Species in T Cell Immunity
Hao-Yun Peng (2021)
Structure of the dihydrolipoamide succinyltransferase (E2) component of the human alpha-ketoglutarate dehydrogenase complex (hKGDHc) revealed by cryo-EM and cross-linking mass spectrometry: Implications for the overall hKGDHc structure.
B. Nagy (2021)
CUT Domain Proteins in DNA Repair and Cancer
Z. Ramdzan (2021)
Mitochondrial Reactive Oxygen Species and Their Contribution in Chronic Kidney Disease Progression Through Oxidative Stress
Hasna Tirichen (2021)
An Update on Developments in the Field of Thiamin Diphosphate-Dependent Enzymes
F. Jordan (2020)
От метаболизма к иммунитету: АФК и другие сигналы
А. Ю. Андреев (2020)
Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease
M. Irazabal (2020)
Regulation of SIRT3 on mitochondrial functions and oxidative stress in Parkinson's disease.
Yanhua Shen (2020)
An integrative approach to the regulation of mitochondrial respiration during exercise: Focus on high-intensity exercise
J. Calbet (2020)
Mitochondrial functions and rare diseases.
L. Dard (2020)
Metabolic ROS Signaling: To Immunity and Beyond
A. Andreyev (2020)
The high expression of MTH1 and NUDT5 predict a poor survival and are associated with malignancy of esophageal squamous cell carcinoma
Jing-jing Wang (2020)
Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention
T. Cunha-Oliveira (2020)
The role of sleep disturbances in depressive-like behavior with emphasis on α-ketoglutarate dehydrogenase activity in rats.
Parastou Kordestani-Moghadam (2020)
Mitochondrial Dysfunction in Astrocytes: A Role in Parkinson’s Disease?
C. Bantle (2020)
Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart
Michael Wagner (2020)
Human mitochondrial DNA repair
E. Sia (2020)
Downregulation of dihydrolipoyl dehydrogenase by UVA suppresses melanoma progression via triggering oxidative stress and altering energy metabolism.
S. Yumnam (2020)
Exclusive neuronal detection of KGDHC-specific subunits in the adult human brain cortex despite pancellular protein lysine succinylation
Á. Dobolyi (2020)
Targeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage
J. Williamson (2020)
Calcium Overload Decreases Net Free Radical Emission in Cardiac Mitochondria.
Quynh V. Duong (2020)
Disruption of mitochondrial functions and oxidative stress contribute to neurologic dysfunction in organic acidurias.
M. Wajner (2020)
Dihydrolipoamide dehydrogenase regulates cystine deprivation-induced ferroptosis in head and neck cancer
Daiha Shin (2020)
Cysteine Switches and the Regulation of Mitochondrial Bioenergetics and ROS Production.
R. Mailloux (2019)
Underlying molecular alterations in human dihydrolipoamide dehydrogenase deficiency revealed by structural analyses of disease-causing enzyme variants.
E. Szabó (2019)See more