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Relationship: 3558

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decrease in mitochondrial oxidative phosphorylation leads to Decrease, ATP production

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decrease in mitochondrial oxidative phosphorylation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decrease, ATP production

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Binding to plastoquinone B site leading to decreased population growth rate via photosystem II inhibition	adjacent	High	High	Li Xie (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 Do not cite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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Lemna minor	Lemna minor	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Pisum sativum	Pisum sativum	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Oxidative phosphorylation (OXPHOS) is the primary mechanism for ATP synthesis in aerobic eukaryotic cells, coupling electron transport chain (ETC) activity to ATP production via the proton motive force (Mitchell, 1961; Nicholls & Ferguson, 2013). Experimental inhibition of ETC complexes (I–IV) or ATP synthase consistently results in decreased mitochondrial membrane potential and reduced ATP generation (Brand & Nicholls, 2011). Chemical uncouplers and respiratory chain inhibitors (e.g., rotenone, antimycin A) produce concentration-dependent declines in cellular ATP levels (Wallace, 2012). Together, biochemical, pharmacological, and bioenergetic studies provide strong mechanistic and quantitative evidence linking impaired OXPHOS directly to decreased ATP production.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence was gathered through targeted literature searches focusing on mitochondrial bioenergetics, electron transport chain inhibition, and ATP synthesis measurements. Studies were selected that quantified both OXPHOS impairment (e.g., membrane potential, respiratory control ratio, complex activity) and ATP levels to ensure direct mechanistic linkage between decreased mitochondrial oxidative phosphorylation and reduced ATP production.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Experimental evidence demonstrates that suppression of mitochondrial respiratory activity results in measurable declines in cellular ATP content. In isolated mitochondria, inhibition of complex I (rotenone), complex III (antimycin A), or complex IV (cyanide) reduces oxygen consumption rates and is accompanied by proportional decreases in ATP synthesis rates (Chance & Williams, 1955; Hatefi, 1985). Measurements of respiratory control ratios show that impaired electron flow diminishes ADP-stimulated phosphorylation efficiency (Nicholls, 2004). Genetic defects affecting ETC components similarly reduce ATP output and cellular energy charge (Wallace, 1999). Together, biochemical, pharmacological, and genetic evidence consistently supports a direct causal linkage between decreased OXPHOS capacity and reduced ATP production.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility of this KER is high because ATP synthesis in aerobic cells is fundamentally dependent on oxidative phosphorylation (OXPHOS). Electron transport through complexes I–IV establishes a proton gradient across the inner mitochondrial membrane, which drives ATP synthase activity (Mitchell, 1961). Any reduction in electron flux decreases proton motive force and directly limits ATP generation (Hatefi, 1985). Experimental measurements of respiratory control demonstrate that impaired coupling efficiency reduces ADP phosphorylation rates (Chance & Williams, 1955). Furthermore, genetic defects in mitochondrial DNA or ETC components consistently result in reduced ATP availability and energetic failure at the cellular level (Wallace, 1999), confirming the mechanistic dependency.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The empirical support of this KER is considered high.

Rationale: Extensive biochemical and pharmacological evidence demonstrates strong dose and temporal concordance between inhibition of mitochondrial oxidative phosphorylation (OXPHOS) and reduction in ATP production. Because ATP synthase activity depends directly on the proton motive force generated by the electron transport chain (ETC), disruption at any ETC complex consistently results in decreased ATP synthesis across experimental systems.

Dose-response concordance: In isolated mitochondria, inhibition of Complex I by rotenone produces an IC₅₀ of ~5–20 nM, with 40–80% ATP reduction observed at 10–100 nM (Hatefi, 1985; Wallace, 1999). Antimycin A (Complex III inhibitor) shows IC₅₀ values of ~1–10 nM and induces >50% ATP depletion at low nanomolar concentrations (Nicholls, 2004). Oligomycin directly inhibits ATP synthase with IC₅₀ ~10–50 nM, reducing ATP production by >70% (Chance & Williams, 1955). These data demonstrate tight quantitative coupling between respiratory inhibition and ATP decline.

Incidence concordance: Across diverse eukaryotic systems, inhibition of ETC complexes I–IV or ATP synthase consistently results in decreased mitochondrial membrane potential and reduced cellular ATP levels, confirming mechanistic dependency (Hatefi, 1985).

Temporal concordance: ATP decline occurs rapidly following OXPHOS inhibition. In isolated mitochondria, suppression of ATP synthesis is detectable within seconds to minutes after inhibitor addition (Chance & Williams, 1955). In intact cells, measurable ATP depletion occurs within 5–30 minutes depending on metabolic reserve capacity (Nicholls, 2004), indicating immediate energetic consequences.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

because ATP levels may be transiently sustained through glycolysis, phosphocreatine buffering, or light reactions in chloroplasts, partially compensating for reduced mitochondrial OXPHOS (Nicholls, 2004; Raghavendra & Padmasree, 2003). Additionally, cell type–specific metabolic flexibility and mitochondrial reserve capacity can modify the quantitative relationship between respiratory inhibition and ATP depletion (Wallace, 1999).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Glycolytic capacity	High vs. low glycolytic flux	High glycolytic capacity buffers ATP decline despite partial OXPHOS inhibition, reducing apparent magnitude of the KER	Nicholls, 2004
Phosphocreatine buffering	Creatine kinase system activity	Phosphocreatine stores transiently maintain ATP levels during acute OXPHOS inhibition, delaying ATP depletion	Nicholls, 2004
Photosynthetic light reactions	Chloroplast ATP production under illumination	In photosynthetic cells, light-driven ATP synthesis can partially compensate for reduced mitochondrial ATP production	Raghavendra & Padmasree, 2003
Mitochondrial reserve capacity	Spare respiratory capacity	Cells with high reserve capacity tolerate partial ETC inhibition before ATP levels decline	Wallace, 1999
Oxygen availability	Normoxia vs. hypoxia	Hypoxia independently limits ETC activity, amplifying ATP decline under OXPHOS impairment	Hatefi, 1985
Substrate availability	NADH/FADH₂ supply from TCA cycle	Limited reducing equivalents exacerbate ATP reduction during ETC inhibition	Hatefi, 1985
Cell type / tissue metabolic demand	High vs. low energy-demand tissues	High-demand tissues (e.g., muscle, neurons) exhibit more rapid ATP depletion when OXPHOS declines	Wallace, 1999

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The quantitative understanding of this KER is high at the mechanistic level. ATP synthesis rate is directly proportional to proton motive force generated by electron transport, and reductions in respiratory flux translate into proportional declines in ATP production (Mitchell, 1961; Nicholls, 2004). Pharmacological inhibition of Complex I–III typically shows IC₅₀ values in the low nanomolar range (≈1–20 nM), with 40–80% ATP reduction observed at concentrations causing ≥50% respiration inhibition (Hatefi, 1985). The response–response relationship is approximately linear under moderate inhibition but becomes nonlinear near complete OXPHOS collapse due to loss of membrane potential and energetic failure (Wallace, 1999).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

The response–response relationship between decreased OXPHOS and ATP production is typically proportional under moderate inhibition, as ATP synthesis depends directly on proton motive force generated by electron transport (Mitchell, 1961). When respiratory inhibition exceeds ~70–80%, ATP decline becomes nonlinear due to membrane potential collapse and loss of phosphorylation capacity (Nicholls, 2004).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The time-scale of this KER is rapid. Following acute inhibition of electron transport, ATP synthesis declines within seconds to minutes in isolated mitochondria due to immediate loss of proton motive force (Chance & Williams, 1955). In intact cells, measurable ATP depletion typically occurs within 5–30 minutes (Nicholls, 2004).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Reduced ATP production activates AMP-activated protein kinase (AMPK), which downregulates anabolic pathways and can suppress mitochondrial activity, reinforcing energy limitation (Hardie, 2011). Conversely, ATP depletion stimulates glycolysis as a compensatory feedback mechanism. Severe ATP loss further destabilizes membrane potential, amplifying OXPHOS impairment.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic applicability: This KER applies broadly to aerobic organisms possessing mitochondria with a functional electron transport chain (ETC) and ATP synthase. It is conserved across eukaryotes including animals, plants, fungi, and protists, as oxidative phosphorylation is the principal mechanism for ATP generation in mitochondria (Mitchell, 1961; Hatefi, 1985). In prokaryotes, analogous coupling between membrane-bound electron transport and ATP synthase occurs, but structural organization differs.

Sex applicability: Not sex-specific. The biochemical mechanism of oxidative phosphorylation and ATP synthase function is conserved across sexes. However, quantitative sensitivity may vary due to sex-specific mitochondrial density, hormonal regulation, or metabolic demand (Wallace, 1999).

Life-stage applicability: Applicable across all life stages that rely on mitochondrial respiration. Rapidly proliferating or high-energy-demand stages (e.g., embryonic, larval, neuronal, muscle tissues) may exhibit greater sensitivity to OXPHOS inhibition due to limited energetic buffering capacity (Nicholls, 2004).

Chemical domain: Relevant to chemicals that impair mitochondrial electron transport or ATP synthase activity, including Complex I–IV inhibitors (e.g., rotenone, antimycin A, cyanide), ATP synthase inhibitors (e.g., oligomycin), and uncouplers of oxidative phosphorylation. Agents acting exclusively on glycolysis without affecting mitochondrial respiration fall outside this KER.

References

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

Brand, M.D., & Nicholls, D.G. (2011). Assessing mitochondrial dysfunction in cells. Biochemical Journal, 435(2), 297–312.

Chance, B., & Williams, G.R. (1955). Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. Journal of Biological Chemistry, 217, 383–393.

Hardie, D.G. (2011). AMP-activated protein kinase: An energy sensor that regulates all aspects of cell function. Genes & Development, 25(18), 1895–1908.

Hatefi, Y. (1985). The mitochondrial electron transport and oxidative phosphorylation system. Annual Review of Biochemistry, 54, 1015–1069.

Mitchell, P. (1961). Coupling of phosphorylation to electron and hydrogen transfer by a chemiosmotic type of mechanism. Nature, 191, 144–148.

Nicholls, D.G. (2004). Mitochondrial membrane potential and aging. Aging Cell, 3(1), 35–40.

Nicholls, D.G., & Ferguson, S.J. (2013). Bioenergetics 4. Academic Press.

Raghavendra, A.S., & Padmasree, K. (2003). Beneficial interactions of mitochondrial metabolism with photosynthetic carbon assimilation. Trends in Plant Science, 8(11), 546–553.

Wallace, D.C. (1999). Mitochondrial diseases in man and mouse. Science, 283(5407), 1482–1488.

Wallace, D.C. (2012). Mitochondria and cancer. Nature Reviews Cancer, 12(10), 685–698.