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Drug induced mitochondrial toxicity in the context of hypoxia

Supervisor: Andrew Murray

Drug-induced mitochondrial perturbation is associated with some clinical toxicities, leading to restrictive labelling and drug withdrawals. It is also a source of costly attrition during late stage drug development. Ideally such toxicity would be identified much earlier, during pre-clinical development, however healthy young animals generally used for in vivo pre-clinical toxicity testing are relatively insensitive to drug-induced mitochondrial perturbation due to their large metabolic reserve capacity and ability to adapt. This is in stark contrast to human patients who are often already challenged metabolically due to co-morbidities, co-medication, lifestyle, age, genetics etc. We therefore aim to better understand how metabolic stressors, that are common in patients, could modify the risk of a compound causing an adverse outcome in vivo. Furthermore, we need better markers of underlying mitochondrial perturbation and metabolic compensation for use in in vivo preclinical toxicology studies. The ultimate aim of this work is to improve patient safety by transforming the pre-clinical detection and risk assessment of mitochondrial-active compounds, thereby reducing the risk of clinical mitochondrial toxicity. Underlying tissue hypoxia/ischemia is a common cause of cellular metabolic stress in multiple patient groups; for example, in cardiovascular disease, NASH, anaemia, peripheral vascular disease, renal disease, lung diseases, diabetic retinopathy & nephropathy and cerebrovascular disease. Cellular responses to hypoxia and mitochondrial perturbation appear to overlap mechanistically and may exacerbate each other. We therefore propose to examine experimental hypoxia as a tractable metabolic stressor relevant to many patient groups; the central hypothesis being that the risk of drug-induced mitochondrial perturbation causing an adverse outcome in vivo is significantly modified by underlying hypoxia. The experimental work will focus on liver and heart as they are important target organs from both drug-induced mitochondrial toxicity and hypoxia/ischemia perspectives and there is evidence for downstream interaction between the mechanisms in these organs.

 

Relevant references

JA Horscroft, et al. Altered oxygen utilisation in rat left ventricle and soleus after 14 days, but not 2 days, of environmental hypoxia. PLOS One. 10:e0138564.

T Ashmore, et al. Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart. J Physiol. 592:4715-31, 2014.

T Ashmore, et al. Suppression of erythropoiesis by dietary nitrate. FASEB J. 29: 1102-1112.

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