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Event: 2118

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Succinate dehydrogenase, inhibited

Short name

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SDH, inhibited

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
hepatocyte

Organ term

Organ term
liver parenchyma

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
succinate dehydrogenase activity		decreased
FAD metabolic process	succinate dehydrogenase complex	decreased
succinate metabolic process	succinate dehydrogenase complex	decreased

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Succinate dehydrogenase inhibition leading to increased insulin resistance	MolecularInitiatingEvent	Evgeniia Kazymova (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult	High

Sex Applicability

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Term	Evidence
Male	High

Key Event Description

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Eukaryotic succinate dehydrogenase (SDH, EC1.3.5.1 (Brenda, IntEnz)) is an enzyme complex comprising four polypeptide chains (SDHA - SDHD) with associated FAD, Fe-S and haem prosthetic groups that catalyses the reversible oxidation (dehydrogenation) of succinate to fumarate with concomitant reduction of ubiquinone to ubiquinol, serving to channel reducing equivalents from succinate, a tricarboxylic acid (TCA) cycle intermediate, to ubiquinol, an intermediate of the mitochondrial electron transfer chain (Du et al, 2023).

The overall reaction:

succinate + ubiquinone = fumarate + ubiquinol

comprises two, reversible half-reactions:

(1) succinate + FAD = fumarate + FADH₂

and:

(2) FADH₂ + ubiquinone = FAD + ubiquinol

each of which is catalysed at a different active site.

The active site of reaction 1 is in the hydrophilic protein SDHA that contains the covalently bound FAD group, and protudes from the inner mitochondrial membrane (IMM) into the mitochondrial matrix, making it available to exchange succinate and fumarate within the TCA cycle. The active site of reaction 2 is in a more hydrophobic region comprising transmembrane domains of proteins SDHC and SCHD that insert complex II into the IMM (Du et al, 2023), making it available to ubiquinol and ubiquinone shuttling within the IMM.

The presence of two distinct and different active sites enables SDH inibition to be effected in at least two ways: by inhibition of either active site, with potentially different biochemical and physiological consequences, and by inhibitors with differing characteristics.

Inhibition of SDH can result in reduction of mitochondrial electron transport, and subsequent inhibition of oxidative phosphorylation (e.g. Chen et al, 2021), and also generation of superoxide in the mitochondria, leading to with subsequently deleterious effects such as initiation of apoptosis or necrosis (Murphy et al, 2009).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Succinate dehydrogenase activity is generally measured by the spectrophotometric detection of colour change in the presence of an electron acceptor, with succinate (succinic acid) as substrate. Alteration in rate of colour change in the presence of a putative inhibitor determining the strength of that inhibition. The fact that the overall reaction is comprised of two consecutive sub-reactions enables the rate of each sub-reaction - and their inhibition - to be measured separately by appropriate choice of electron acceptor in the presence of succinate as a substrate (e.g. Miyadera et al, 2003). Activities are frequently measured in isolated mitochondria, in order to reduce interference by extra-cytosolic enaymes and intermediates; mitochondria can be sonicated to obviate rate limitation by mitochondrial upake of succinate (e.g. Guo et al, 2016).

SDH activity

Succinate dehydrogenase (SDH) activity corresponds to reaction (1), above. It can be measured by use of the water-soluble dye 2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide (MTT) in the presence of the intermediate electron carrier phenazine methosulfate (PMS), to intercept electrons before their transport to ubiquinone, and convey them to MTT, which changes colour following its reduction.

SQR activity

Succinate quinone reductase (SQR) activity corresponds to the overall reaction (i.e. 1 and 2), above. It can be measured by reduction of 2,6-dichlorophenolindophenol (DCPIP) in the presence of the 2,3-dimethoxy-6-methyl-1,4-benzoquinone (UQ₂), which accepts electrons from the ubiquinone reduction site and transfers them to DCPIP, thus being a measure of the rate of the entire reaction catalysed by complex II.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

SDH inhibition by phthalate esters has been measured and quantified in mitochondria of hepatocytes of adult male CD rats (Melnick and Schiller, 1982; Melnick and Schiller, 1985). Inter-species differences in SDH structure may lead to different susceptibilities in different taxa.

SDH inhibition has been demonstrated by lonidamine, 3-nitroproprionic acid (3-NPA) and 2-thenoyltrifluoroacetone (TTFA) in DB-1, HepG2, HCT116 and HeLa cells, and by lonidamine in mitochondria isolated from adult mouse liver (Guo et al, 2016).

References

List of the literature that was cited for this KE description. More help

Brenda, "Information on EC 1.3.5.1 - succinate dehydrogenase", https://www.brenda-enzymes.org/enzyme.php?ecno=1.3.5.1, accessed 28/04/2023.

Chen, L. et al (2021) "Citrus-derived DHCP inhibits mitochondrial complex II to enhance TRAIL sensitivity via ROS-induced DR5 upregulation", Journal of Biological Chemistry, Vol 296, 100515

Du, Z. et al (2023) "Structure of the human respiratory complex II", Proceedings of the National Academy of Sciences", Vol 120, e2216713120.

Guo, L. et al (2016) "Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine", Journal of Biological Chemistry, Vol 291. pp42-57.

IntEnz, "IntEnz Enzyme Nomenclature, EC 1.3.5.1", https://www.ebi.ac.uk/intenz/query?cmd=SearchID&id=1525&view=INTENZ, accessed 28/04/2023.

Melnick, R.L. and Schiller, C.M. (1982), "Mitochondrial toxicity of phthalate esters", Environmental Healh Perspectives, Vol 45, pp51-56.

Melnick, R.L. and Schiller, C.M. (1985), "Effect of phthalate esters on energy coupling and succinate oxidation in rat liver mitochondria", Toxicology, Vol 34, pp13-27.

Miyadera, H. et al (2003) "Atpenins, potent and specific inhibitors of mitochondrial complex II (succinateubiquinone oxidoreductase)", Proceedings of the National Academy of Sciences, Vol 100, pp473-477.

Murphy, M.P. (2009), "How mitochondria produce reactive oxygen species", Biochemical Journal, Vol 417, pp1-13.