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Relationship: 3134
Title
Increase, Mitochondrial dysfunction leads to Increase, Cytotoxicity (renal tubular cell)
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Inhibition of mitochondrial DNA polymerase gamma leading to kidney toxicity | adjacent | High | Low | Angela Mally (send email) | Under development: Not open for comment. Do not cite | Under Development |
| Inhibition of mitochondrial electron transport chain (ETC) complexes leading to kidney toxicity | adjacent | Not Specified | Not Specified | Baki Sadi (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Mitochondria are an essential organelle in ROS production, ATP production, and have a crucial role in regulating both apoptotic and necrotic death (Bhatia, Capili, and Choi, 2020; Wang et al., 2016; Gao et al., 2019). This is particularly notable for renal tubular cells due to their high energy demands for filtration (Cohen, 1986). When mitochondria are damaged and their membrane potential is dissipated, the mitochondrial permeability transition pore (mPTP) is opened and they release cytochrome c (Cyt c), pro-apoptotic caspases, and apoptosis-inducing factor (AIF) (Mao et al., 2010; Galluzzi et al., 2018; Garrido et al., 2006). Cyt c is a protein that triggers apoptosis or necrosis by allosterically activating apoptosis-protease activating factor 1 (APAF 1) (Mao et al., 2010; Galluzzi et al., 2018; Garrido et al., 2006). APAF 1 is then able to cleave caspases 9 and 3, which lead to the induction of a caspase cascade that triggers apoptosis (Mao et al., 2010; Galluzzi et al., 2018; Garrido et al., 2006). Caspase-independent apoptosis is also triggered by the opening of the mPTP, causing the release of AIF which triggers DNA condensation into chromosomes and degradation in a characteristic manner (Sevrioukova, 2011). Mitochondrial dysfunction therefore leads to not only further oxidative stress, but also to cell death (Bhatia, Capili, and Choi, 2020; Wang et al., 2016; Zhan et al., 2013).
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
The evidence of biological plausibility between increased mitochondrial dysfunction and renal tubular cytotoxicity is strong, as it is detailed in numerous review articles (Bhatia, Capili, and Choi, 2020; Zhan et al., 2013; Gao et al., 2019; Garrido et al., 2006). Mitochondrial dysfunction includes the inhibition of calcium accumulation in the mitochondria, loss of mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore, increased mitochondrial swelling, decreased ATP production, and mitochondrial depolarization (Bhatia, Capili, and Choi, 2020; Zhan et al., 2013; Gao et al., 2019; Garrido et al., 2006).
The induction of the permeability transition of the mitochondrial inner membrane in particular leads to the opening of the mitochondrial permeability transition pore (Mao et al., 2010). This allows the release of several pro-apoptotic molecules to the cytosol, including Cyt c, apoptosis-inducing factor (AIF), and the pro-caspases-2, -3, and -9 (Garrido et al., 2006). Mitochondrial dysfunction can trigger apoptosis through the use of caspase-dependant and independent pathways (Bhatia, Capili, and Choi, 2020; Zhan et al., 2013; Gao et al., 2019; Garrido et al., 2006). The caspase-dependant pathway of apoptosis induction requires Cyt c. Cyt c is an electron carrier in the mitochondrial electron transport chain (Mao et al., 2010). When released from the mitochondrial it is able to allosterically activate a protein called apoptosis protease activating factor-1 (APAF-1) (Mao et al., 2010). APAF-1 is required for the proteolysis of caspases-9 and -3, which are able of inducing a caspase cascade that results in apoptosis (Mao et al., 2010). The opening of the MPTP is also able to induce a cascade-independent method of cell death via the protein AIF (Mao et al., 2010; Sevrioukova, 2011). AIF is a protein that is normally located on the inner mitochondrial membrane of the mitochondria (Sevrioukova, 2011). When released to the cytosol, AIF undergoes proteolysis and is transported to the nucleus of the cell and induces the condensation of chromatin, as well as characteristic degradation of the cell’s DNA to induce apoptosis in a caspase-independent manner (Sevrioukova, 2011)
Empirical Evidence
One article found that pig kidneys treated with varying concentrations of cisplatin for 10 minutes showed that mitochondrial membrane potential was significantly decreased at a concentration of only 10 μM and cell viability was not significantly decreased until 30 μM (Kruidering et al., 1997). Another article found that treatment with cadmium for 3 hours on human kidney cells caused significant inhibition of resting respiration rates at a concentration of 100 μM and significant inhibition of cell viability at a concentration of 500 μM (Belyaeva et al., 2012). An article examining rat brain mitochondria treated with uranium for 1 hour also showed that treatment with 50 μM uranium caused significant increase in mitochondrial membrane potential and treatment with 100 μM uranium induced a significant decrease in cell viability (Shaki et al., 2012). A study examining the effects of silver nitrate treatment on human bronchial epithelial cells, showed that treatment for 24 hours induced significant mitochondrial dysfunction at a dose of 1.0 μM and cell death was significantly increased at a dose of 5.0 μM (Miyayama et al., 2013). An article investigating the nephrotoxic effects of arsenic on isolated rat kidneys also found that mitochondrial membrane potential (MMP) collapse and Cyt c release were both significantly elevated when the rat kidney cells were treated with 50 and 100 μM for 1 hour, respectively (Hassani et al., 2015).
Temporal concordance
There are currently few articles available that show temporal concordance for mitochondrial dysfunction leading to renal tubular cytotoxicity. One article assessed the effect of uranyl nitrate treatment on normal rat kidney proximal cells and found that mitochondrial membrane potential was significantly decreased after 18 hours of treatment with 600 μM of uranyl nitrate while cell viability was not significant until 24 hours of treatment (Thiébault et al., 2007).
Incidence concordance
Another article found that treating human kidney cells with mercury for 3 hours caused significant inhibition of resting respiration rates and significant inhibition of cell viability both at a concentration of 50 μM (Belyaeva et al., 2012). Copper nanoparticles were also able to induce notable mitochondrial dysfunction and nephrotoxicity in pig kidneys treated for 12 hours with 20 and μg/mL (Zhang et al., 2018). Another article investigated the effects of treatment with varyiousheavy metal nanoparticles and micrometer particles on an alveolar type-II epithelial cell line (Karlsson et al., 2009). They found that iron(II) oxide nanoparticles had a 4.1-fold increase in mitochondrial depolarization and a 3.5-fold increase in non-viable cells.
Uncertainties and Inconsistencies
- In an article studying the nephrotoxic effects of cisplatin treatment in rat kidneys, they found that treatment with 10 mg/kg bodyweight of cisplatin for 72 hours caused only a 0.3-fold decrease in the level of ATP content in the cell but induced a 1.8-fold increase in the level of executioner caspase-3 activity (Santos et al., 2007).
- In an article assessing the effects of depleted uranium on human kidney cells, mitochondrial membrane potential was increased significantly by only 3.9-fold when cells were treated with 500 μM for 24 hours (Hao et al., 2014). However, under the same conditions, cytotoxicity was elevated 6.5-fold. (Hao et al., 2014).
- A study assessing depleted uranium treatment on human embryonic kidney cells also found that only a 3.6-fold increase in membrane potential occurred for cells treated with depleted uranium, while a 5.6-fold increase was seen in cell death compared to the control (Hao et al., 2016).
- Another article investigated the effects of treatment with various heavy metal nanoparticles and micrometer particles on an alveolar type-II epithelial cell line. In addition, copper oxide nanoparticles and micrometer particles both showed 27.1-fold and 12.1-fold increases in mitochondrial depolarization while cytotoxicity was increased by 56.4-fold and 18.2-fold, respectively (Karlsson et al., 2009).
Known modulating factors
There are several known modulating factors that affect the relationship between mitochondrial dysfunction and cell death. One known modulating factor of this variation is mitochondrial biogenesis (Jornayvaz and Shulman, 2010). Mitochondrial biogenesis is the ratio of growth, division, and recycling of existing mitochondria in the cell. Mitochondrial biogenesis itself is influenced by a variety of factors such as exercise levels, cell division, low temperature, caloric restriction, and as is discussed in this AOP, oxidative stress . As a result of changes in these factors, the mitochondrial content, as well as sizes and masses of each of the organelles, is altered . For example, it is generally accepted that increased exercise in an organism increases mitochondrial content and functioning, as there is an increased energy need in those organisms . Therefore, an organism with increased exercise habits would have a less steep slope in the relationship between mitochondrial dysfunction and cell death, as the mitochondrial dysfunction would not be able cause cell death as quickly, since mitochondrial content would be higher requiring a longer time period to accumulate sufficiently to induce apoptosis . This would allow the cell to undergo mitophagy of the injured mitochondria while still continuing to produce adequate energy to keep the cell alive . Similarly, if a cell had just divided, it would be less prepared and capable of dealing with mitochondrial dysfunction, which would allow it to accumulate much faster and would therefore increase the slope between mitochondrial dysfunction and cell death (Jornayvaz and Shulman, 2010).
Some diseases are also known to modulate this relationship, such as early aging and diabetes (Pizzorno, 2014). These diseases increase the slope of the relationship between mitochondrial dysfunction leading to oxidative stress due to the fact that they induce faster accumulation of mitochondrial dysfunction via increased levels of oxidative stress and faster accumulation of mitochondrial DNA damage leading to earlier mitochondrial dysfunction (Nissanka and Moraes, 2018; Zelenka, Dvorak, and Alan, 2015; Wei et al., 2015; Kudryavtseva et al., 2016; Forbes and Thorburn, 2018; Schiffer and Friederich-Persson, 2017).
Quantitative Understanding of the Linkage
Response-response Relationship
There is a strong, positive correlation between the increase in mitochondrial dysfunction and the increase in cytotoxicity. This was demonstrated by an article which plotted MTT cell viability assay results and LDH concentration in the cell culture media which showed a negative correlation with a slope of -0.99 and a correlation coefficient of 0.97 (Wang et al., 2016).
Time-scale
There has not yet been an identified time-scale for this relationship. Further research will be required in order to determine the time-scale.
Known Feedforward/Feedback loops influencing this KER
There are no feedforward or feedback loops that are known to influence this KER.
Domain of Applicability
The domain of applicability only includes vertebrates, as invertebrates and non-animals do not have kidneys (Mahasen, 2016).
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