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Inhibition, NADH-ubiquinone oxidoreductase (complex I) leads to N/A, Mitochondrial dysfunction 1
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits||adjacent||High||Moderate||Andrea Terron (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
Inhibited CI is unable to pass off its electron to ubiquinone and it cannot translocate protons across the mitochondrial inner membrane. This creates a back-up of NADH within the mitochondrial matrix (Brown and Borutaite, 2004). This leads to an arrest of the citric acid cycle and a failure to build a proton gradient (mitochondrial membrane potential, Δψm) across the inner membrane. This results in impaired ATP production. In addition, the direct transfer of electrons from CI to oxygen is increased. This leads to oxidative stress as ROS (e.g. superoxide, hydrogen peroxide) are produced, which can damage DNA, proteins, lipids and other cell components and function (Sanders et al., 2014).
Evidence Supporting this KER
The weight of evidence supporting the relationship between inhibition of CI and mitochondrial dysfunction is strong. The mechanisms behind this KER are partially understood and well documented based on in vitro as well as in vivo experiments (e.g., Sanders et al., 2014), complemented by data from human post-mortem PD brain evaluations (Parker et al., 1989; Greenamyre et al., 2001; Sherer et al., 2003; Schapira et al., 1989).
The biological plausibility that inhibition of CI activity triggers mitochondrial dysfunction is strong. It is well understood, how the inhibition of CI can lead to mitochondrial dysfunction as measured by: a) decreased oxygen consumption, b) decrease or loss of ATP production, c) decrease of Δψm, d) the loss of mitochondrial protein import and protein biosynthesis, e) reduced activities of enzymes of the mitochondrial respiratory chain and the Krebs cycle, f) elevated levels of ROS, g) the loss of mitochondrial motility, causing a failure of mitochondria to re-localize to sites of increased energy demands (such as synapses), h) destruction of the mitochondrial network, i) increased mitochondrial uptake of Ca2+ causing mitochondrial Ca2+ overload (Graier et al., 2007) and opening of mitochondrial PTP, (j) rupture of the mitochondrial inner and outer membranes, leading to release of mitochondrial pro-death factors, including cytochrome c, AIF and endonuclease G (Braun, 2012; Martin, 2011; Correia et al., 2012; Cozzolino et al., 2013). These pathological mechanisms are extremely well studied.
Uncertainties and Inconsistencies
Some studies suggest that rotenone may have effects other than CI inhibition, and it has been claimed that rotenone induces microtubule disruption, rather than ETC CI inhibition (Feng, 2006; Ren et al., 2005). Some studies suggested that there was no evidence for significant change in mitochondrial CI function in PD patients' brains (Jenner et al., 1992). It is still unclear whether the site of superoxide production in CI inhibited mitochondria is CI itself or not (Singer and Ramsay, 1994).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Mitochondrial CI in eukaryotes has highly conserved subunit composition based on protein databases (Cardol, 2011). The characterization of induced mitochondrial dysfunction phenotypes in zebrafish was studied in the presence of CI and CII inhibitors (Pinho et al., 2013). Exposure of Caenorhabditis elegans (C. elegans) to rotenone, reduced bioluminescence (an assay for mitochondrial dysfunction) after both relatively short (2 hr) and longer exposures (24 hr) to a range of concentrations. A sharp decline in bioluminescence (maximal inhibition) relative to controls occurred at the lowest rotenone concentration of 2.5 μM. This decline in bioluminescence was consistent with reduced cellular ATP (Lagido et al., 2015). The results obtained from C. elegans exposed to rotenone suggested that chronic exposure to low concentration (2 or 4 μM) caused mitochondrial damage through persistent suppression of mitochondrial biogenesis and mitochondrial gene expression leading to mitochondrial dysfunction that contributed to DA neuron degeneration (Zhou et al., 2013).
Drosophila melanogaster has been proven suitable to study signaling pathways implicated in the regulation of mitochondrial function and integrity, such as the PINK1/parkin pathway (controlling mitochondrial integrity and maintenance), DJ-1 and Omi/HtrA2 genes (associated with the regulation of mitochondrial functionality). Notably, PINK1, PARKIN, and DJ-1 genes are associated with recessive forms of PD (Guo, 2012). Drosophila flies lacking DJ-1 result to be viable, but show an increased sensitivity to oxidative stress induced upon rotenone or Paraquat (an herbicide inducer of CI-dependent ROS) feeding (Menzies et al. 2005; Meulener et al. 2005; Meulener et al. 2006). Moreover, it has been reported in Drosophila that inhibition of CI by mean of sublethal chronic exposure to rotenone (<750 μM) via the feeding medium caused a selective loss of DA neurons in all of the brain regions and locomotor impairments, while L-dopa (3,4-dihydroxy-L-phenylalanine) rescued the behavioral deficits (but not neuronal death) (Coulom and Birman, 2004). MPTP causes Parkinsonism in primates including humans. However, rodents (rats) are much less susceptible to MPTP+ but are fully susceptible to MPP+ (due to the differences in toxicokineticks). In all species, CI inhibition leads to mitochondrial dysfunction. Mitochondrial dysfunction is an universal event occurring in cells of any species (Farooqui and Farooqui, 2012).
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