API

Relationship: 922

Title

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Peptide Oxidation leads to N/A, Mitochondrial dysfunction 1

Upstream event

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Peptide Oxidation

Downstream event

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N/A, Mitochondrial dysfunction 1

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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The mitochondrion consist of a plethora of antioxidant enzymes to defend against oxidative stress, such as catalases, which has been found in the liver, glutathione peroxidase, and thioredoxin peroxidase [1] [2]. At the same time, the mitochondrion itself is one of the main sources of intracellular ROS formation [3].

NAD(P)H plays a central role in the redox state of the mitochondrion: NADP is reduced, in part, by the activity of the NADH/NADP transhydrogenase that functions as a proton pump [1] and has a reductive effect on glutathione and thioredoxin. This directly links mitochondrial coupling and the membrane potential to the redox potential. As a consequence, an imbalance in the NAD(P) redox status can lead to mitochondrial permeability transition (MPT), a nonselective permeabilization of the inner mitochondrial membrane [4]. An imbalance of the redox state of these pyridine nucleotides and thus condition of oxidative stress can lead to an increased influx of Ca2+, which in turn facilitates activation of the mitochondrial permeability transition pore, leading to apoptosis [5] [6].

Evidence Supporting this KER

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Biological Plausibility

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Overwhelming the mitochondrial antioxidant defence system and subsequent uncoupling of the respiratory chain leads to MPT, resulting in loss of matrix components, impairment of mitochondrial functionality and substantial induction of apoptosis [4].

Empirical Evidence

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Include consideration of temporal concordance here

A direct effect of oxidative stress induction (by using t-butylhydroperoxide TBH) on the opening of the mitochondrial permeability transition pore has been reported using rat liver mitochondria [7]. This was found to lead to an increase in the mitochondrial membrane potential, which could be partly inhibited by addition of the antioxidant GSH [8]. Cell treatment with a lysosomal inhibitor was found to delay the production of ROS that act on mitochondria, thus mitochondria-related cell death was delayed [9]. Superoxide-radical-triggered increase in Ca2+ uptake to the mitochondrion was found to precede loss of mitochondrial membrane potential, which was independent of other oxidants and mitochondrially derived ROS, as determined by using respective inhibitors. This work shows the specific effects of external and not mitochondrially derived ROS on mitochondrial damage [10].

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Quantitative understanding of this KER is low. Inhibition of the ROS source could delay mitochondrial damage, and treatment with an antioxidant could partly inhibit the effect on the mitochondrion.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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[10]: rat

[7]: rat

[8]: rat

[9]: mouse

References

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  1. 1.0 1.1 Kowaltowski AJ, de Souza-Pinto NC, Castilho RF, Vercesi AE. Mitochondria and reactive oxygen species. Free Radic Biol Med. 2009 Aug 15;47(4):333-43
  2. M. Salvi, V. Battaglia, A.M. Brunati, N. La Rocca, E. Tibaldi, P. Pietrangeli, L. Marcocci, B. Mondovì, C.A. Rossi, A. Toninello. Catalase takes part in rat liver mitochondria oxidative stress defense. J. Biol. Chem., 282 (2007), pp. 24407–24415
  3. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007 Jun 15;462(2):245-53
  4. 4.0 4.1 Kowaltowski AJ, Castilho RF, Vercesi AE. Mitochondrial permeability transition and oxidative stress. FEBS Lett. 2001 Apr 20;495(1-2):12-5
  5. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999 Jul 15;341 (Pt 2):233-49
  6. Hüser J, Rechenmacher CE, Blatter LA. Imaging the permeability pore transition in single mitochondria. Biophys J. 1998 Apr;74(4):2129-37
  7. 7.0 7.1 Halestrap AP, Woodfield KY, Connern CP. Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem. 1997 Feb 7;272(6):3346-54
  8. 8.0 8.1 Hüser J, Rechenmacher CE, Blatter LA. Imaging the permeability pore transition in single mitochondria. Biophys J. 1998 Apr;74(4):2129-37
  9. 9.0 9.1 Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem. 2010 Jan 1;285(1):667-74
  10. 10.0 10.1 Madesh M, Hawkins BJ, Milovanova T, Bhanumathy CD, Joseph SK, Ramachandrarao SP, Sharma K, Kurosaki T, Fisher AB. Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis. J Cell Biol. 2005 Sep 26;170(7):1079-90