Mitochondrial Metabolism: Using a Systems Approach to Relate in vitro Findings to in vivo Outcomes

Mitochondrial toxicity is responsible for many drug candidates failing or requiring "Black box" warnings. Whilst cell cultures are increasingly used initially to predict toxicity, the results can differ from later in vitro studies, sometimes leading to costly failures. The reasons for these differences are unknown. GlaxoSmithKline has accrued large data sets measuring mitochondrial- and cyto-toxicity of many compounds in in vitro cell-based systems, isolated rat liver mitochondrial studies, and in vivo rat studies. The aim of this PhD is to integrate, analyse, and model these complex multisystem datasets to build a picture of how mitochondrial biochemistry differs between in vitro and in vivo systems. These models will be used to improve usefulness of in vitro models, and also address "3R's" of animal research.

Fundamental Question 1: What are the key biochemical changes underlying any shift in mitochondrial function in conditioned cells and do these reflect a more physiological respiratory state or an alternate adapted state?

Fundamental Question 2: What are the key functional and biochemical signals that distinguish very early mitochondrial perturbation in vitro from cytotoxicity and critically how do these relate to early signs (e.g. biochemical or functional markers) of mitochondrial perturbation in vivo?