| dc.description.abstract | Mitochondria are key players in several kinds of tissue injury, and are even the site of
mechanism of certain diseases. In this work we introduce new models of mitochondrial
ATP generation in multiple tissues, including liver hepatocytes and the medullary thick
ascending limb in the kidney. Using this model, we predict these tissues' responses to hypoxia,
uncoupling, ischemia-reperfusion, and oxidative phosphorylation dysfunction. Our results
suggest mechanisms explaining differences in robustness of mitochondrial function across
tissues.
The medullary thick ascending limb and proximal tubule in the kidney both experience
a high metabolic demand, while having lower baseline activity of oxidative phosphorylation
relative to the liver. These factors make these tissues susceptible to dysfunction in Complex
III. A lower baseline oxygen tension observed in the thick ascending limb makes it susceptible
to Complex IV. On the other hand, since the liver lacks these risk factors, and has higher
baseline rates of glycolysis, it is less susceptible to all kinds of oxidative phosphorylation
dysfunction.
Ischemia-reperfusion is an intriguing example of a non-equilibrium behaviour driven by
a change in tissue oxygen tension. Ischemia involves prolonged hypoxia, followed by the
sudden return of oxygen during reperfusion. During reperfusion, we predict that the build
up of succinate causes the electron transport chain in the liver to temporarily be in a highly
reduced state. This can lead to the production of reactive oxygen species. We accurately
predict the timescale on which the electron transport chain is left in a reduced state, and we
observe levels of reduction likely to lead to reactive oxygen species production.
Aside from the above, we predict thresholds for ATP depletion from hypoxia, and we
predict the consequences for oxygen consumption of uncoupling. We nd that once again, the
kidney tissues considered are more at risk from hypoxia. We predict that hypoxia represents
a danger of ATP depletion in the proximal tubule below 10 mmHg of oxygen partial pressure,
and in the thick ascending limb below 3 mmHg.
We examine at length the effects of diabetes on the liver and kidney, and we nd that
it may leave the kidney especially at greater risk for ATP depletion and reactive oxygen
species formation. This is particularly true during hypoxia (and uncoupling in the case of
ATP depletion).
Our modelling efforts indicate the viability of modelling mitochondrial pathologies with
mechanistic models. We demonstrate that even simple models of mitochondrial dysfunction
may effectively reproduce experimental results. | en |
