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Event: 1543

Key Event Title

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

Mitochondrial Complex IV inhibition

Short name

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

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

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
Mitochondrial complex inhibition leading to liver injury	MolecularInitiatingEvent	Wanda van der Stel (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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The mitochondrial complex IV (Cytochrome c oxidase) is an enzyme complex located in the inner membrane of mitochondria. It is the forth out of 5 complexes that together form the mitochondrial respiratory chain. It consists out of multiple subunits of cytochrome c oxidase, including cytochrome a and cytochrome a3.

The combination of these subunits catalyze following process:

The cytochrome c oxidase is involved in the process of oxidizing reduced cytochrome c to its oxidized form. A process that results in a free electron.

4 oxidation rounds results in enough electron to reduce 1 molecule oxygen to 2 molecules water.

The electron transfer in this process mediates the translocation of protons from the mitochondrial matrix through the inner membrane to the intermembrane space. The created proton gradient will be used to catalyze the reaction in which ADP is converted into ATP.

The initiation event is the reversibly or irreversibly interaction to any of the subunits in the mitochondrial complex IV, leading to an perturbation of the electron flow and an absence of proton transport via this complex.

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

Complex inhibition assays specifically for complex IV The activity of complex IV is always tested in the bovine heart mitochondria provided within the kit. The kit relies on the following detection of complex IV activity: The reduction of cytochrome c, which leads to a reduction in absorbance at 550nm can be measured.
Mitochondrial Membrane potential using fluorescent dyes. Positive charged molecules will accumulated in the mitochondria in an inverse proportion as the membrane potential. More polarised mitochondria will accumulate more dye (Rhodamine123, TMRE, TMRM) - leading to a higher fluorescent signal - and the absence of membrane potential leads to an absence of fluorescent signal. An exception is the dye JC1, because this dye has green fluorescence when present in low concentrations (depolarisation) and red fluorescence when accumulated (hyperpolarized

Measurements

Complex inhibition assays

Cayman MitoCheck MitoCheck® Complex IV Activity Assay Kit (Item No. 700990)
Abcam MitoTox™ Complex IV OXPHOS Activity Assay Kit (ab109906) Complex IV Human Enzyme Activity Microplate Assay Kit (ab109909)
BioVision Cytochrome Oxidase Activity Colorimetric Assay Kit (K287)

Membrane potential dyes

Perry, 2011, mitochondrial membrane potential probes and proton gradient
Mitra, 2010, analysis of mitochondrial dynamics and functions using imaging approaches

Domain of Applicability

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References

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