Supramolecular organization of tricarboxylic acid cycle enzymes

Lyubarev, A. E.; Bi, Kurganov

doi:10.1016/0303-2647(89)90038-5

Cited by 52 publications

(37 citation statements)

References 33 publications

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“…Studies have proposed that several enzymes of the Krebs cycle also, like the respirasome, exist in a supramolecular complex called the metabolon (31)(32)(33)(34)(35)(36)(37)(38), attached to the matrix face of the inner mitochondrial membrane by SDH/Complex II, as the anchor site for assembly of the metabolon on the membrane (33). In addition, 2-OGDH was proposed to play a key role in metabolon formation, with two association sites on opposite sides in its interaction with the membrane.…”

Section: Coupling Of Sdh/complex II Activity To Metabolism Via Krebs mentioning

confidence: 99%

Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

et al. 2011

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Succinate:quinone reductase (SQR) of Complex II occupies a unique central point in the mitochondrial respiratory system as a major source of electrons driving reactive oxygen species (ROS) production. It is an ideal pharmaceutical target for modulating ROS levels in normal cells to prevent oxidative stress-induced damage or alternatively,increase ROS in cancer cells, inducing cell death.The value of drugs like diazoxide to prevent ROS production,protecting normal cells, whereas vitamin E analogues promote ROS in cancer cells to kill them is highlighted. As pharmaceuticals these agents may prevent degenerative disease and their modes of action are presently being fully explored. The evidence that SDH/Complex II is tightly coupled to the NADH/NAD+ ratio in all cells,impacted by the available supplies of Krebs cycle intermediates as essential NAD-linked substrates, and the NAD+-dependent regulation of SDH/Complex II are reviewed, as are links to the NAD+-dependent dehydrogenases, Complex I and the E3 dihiydrolipoamide dehydrogenase to produce ROS. This review collates and discusses diverse sources of information relating to ROS production in different biological systems, focussing on evidence for SQR as the main source of ROS production in mitochondria, particularly its relevance to protection from oxidative stress and to the mitochondrial-targeted anti cancer drugs (mitocans) as novel cancer therapies [corrected].

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Section: Coupling Of Sdh/complex II Activity To Metabolism Via Krebs mentioning

confidence: 99%

Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

et al. 2011

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“…KGDHC is an integral mitochondrial enzyme tightly bound to the inner mitochondrial membrane on the matrix side (Maas and Bisswanger, 1990). It binds (specifically) to complex I of the mitochondrial respiratory chain (Sumegi and Srere, 1984) and may form a part of the TCA cycle enzyme supercomplex (Lyubarev and Kurganov, 1989). The mitochondrial TCA cycle enzymes aconitase, succinate dehydrogenase (SDH), and KGDHC itself are sensitive to oxidative inactivation both in vitro and in vivo (Tretter and Adam-Vizi, 2000;Gibson et al, 2002;Sadek et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

Starkov¹,

Fiskum²,

Chinopoulos³

et al. 2004

J. Neurosci.

623

448

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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 H 2 O 2 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, ␣-ketoglutarate supported the highest rate of H 2 O 2 production. In the absence of ADP or in the presence of rotenone, H 2 O 2 production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of ␣-ketoglutarate. Isolated mitochondrial ␣-ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H 2 O 2 . NAD ϩ inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H 2 O 2 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 H 2 O 2 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.

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“…Furthermore, several consecutive enzymes of a metabolic pathway can join together in a transient complex to channel substrates between them. Such a supercomplex, coined ‘metabolon’ by Paul Srere over 30 years ago 26 , can be found for Krebs cycle enzymes 27, 28 or demonstrated in vitro by tethering the sequential enzymes of glycolysis on a surface 29 .…”

Section: Channeling: a Smart Strategy To Maximize Efficiencymentioning

confidence: 99%

The advantage of channeling nucleotides for very processive functions

et al. 2017

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Nucleoside triphosphate (NTP)s, like ATP (adenosine 5'-triphosphate) and GTP (guanosine 5'-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP-or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised 'microcompartments', where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, . is very processive. Here, we summarise the evidence for these conclusions i.e and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases.

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Supramolecular organization of tricarboxylic acid cycle enzymes

Cited by 52 publications

References 33 publications

Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

Inhibitors of Succinate: Quinone Reductase/Complex II Regulate Production of Mitochondrial Reactive Oxygen Species and Protect Normal Cells from Ischemic Damage but Induce Specific Cancer Cell Death

Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

The advantage of channeling nucleotides for very processive functions

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