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Regulation of mitochondrial function in response to hypoxia (Andrew Murray)

Supervisor: Andrew Murray

Oxidative tissues, such as heart, skeletal muscle and liver, are dependent upon a constant supply of oxygen to support mitochondrial pathways of energy metabolism. Under conditions of low tissue oxygen, such as those experienced by a climber at high altitude or a critically ill patient, a process of acclimatisation occurs in order to maintain energetic and redox homeostasis. Our work has shown that changes in mitochondrial function underpin this response, and that these changes occur in a characteristic, time-dependent manner, with mitochondrial density and function preserved with relatively short-term hypoxic exposure and altered with more prolonged exposure, particularly in response to more extreme hypoxia. Such changes include alterations in tissue mitochondrial density and distribution, altered electron transport chain activity, changes in substrate preference and altered efficiency of oxygen utilisation. The cellular response to hypoxia is mediated by the hypoxia-inducible factor (HIF) family of transcription factors, which themselves show a distinct time-course of activation, termed the HIF-switch, with HIF-1 mediating the short term response to hypoxia and HIF-2 mediating the response to more sustained exposure. This project will use genetic tools, high-resolution respirometry and cutting-edge metabolomic technologies to understand the molecular mechanisms underlying the time-dependent metabolic responses to tissue hypoxia. Parallel studies will be carried out in critically ill human subjects and healthy subjects exposed to hypobaric hypoxia in collaboration with the Xtreme Everest Research Group. The results arising from this work will be of interest to clinical collaborators, basic science researchers and our industry collaborators at GSK and AstraZeneca.

Relevant references

JA Horscroft, SL Burgess, Y Hu, AJ Murray, (2015), 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, BO Fernandez, C Branco‐Price, JA West, AS Cowburn, LC Heather, JL Griffin, RS Johnson, M Feelisch, AJ Murray, (2014), Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart, J Physiol 21: 4715-4731

DZ Levett, EJ Radford, DA Menassa, EF Graber, AJ Morash, H Hoppeler, K Clarke, DS Martin, AC Ferguson-Smith, HE Montgomery, MP Grocott, AJ Murray, (2012), Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest, FASEB J 26: 1431-144



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