Cardiovascular Research

Dr Assegid Garedew
Dr Christoph Schmitt

Mitochondria and the bioenergetic status of activated macrophages.

We are interested in the mechanisms by which mitochondria regulate cell function and death in response to activation by pro-inflammatory agents. We mainly use biochemical, imaging, respirometry and cell biology approaches in our studies.

We have recently shown that activation of macrophages by treatment with interferon (IFN)gamma and lipopolysaccharide (LPS) leads to a progressive mitochondrial defect characterized by inhibition of oxygen consumption and a decrease in the generation of ATP by oxidative phosphorylation. These changes are dependent on the generation of nitric oxide (NO) by an inducible NO synthase (iNOS) which, as it increases, becomes a significant consumer of oxygen. Furthermore, in these activated cells there is a biphasic stabilization of the hypoxia-inducible factor HIF-1alpha, the second phase of which is also dependent on the presence of NO. The mitochondrial defect and stabilization of HIF-1alpha synergize to activate glycolysis which, at its maximum, generates ATP in quantities greater than that produced by non-activated cells. Nevertheless, the amount of ATP generated by activated cells is not sufficient to fulfil their energy requirements, thus leading to a progressive energy deficit with the consequent inhibition of cell proliferation and death.

Selected publications

Garedew A, Henderson SO, Moncada S (2010). Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death Differ. 2010 Mar 26. Epub ahead of print

Garedew A, Kämmerer U, Singer D (2009) Response of malignant and placental cells to changes in oxygen concentration. Respir Physiol Neurobiol. 165(2-3):154-60.

Garedew A and Moncada S (2008). Mitochondrial dysfunction and HIF-1a stabilization in inflammation. J.Cell Sci. 121:3468-75.

Hütter E, Unterluggauer H, Garedew A, Jansen-Dürr P, and Gnaiger E (2006). High resolution respirometry– a modern tool in aging research. Exp. Gerontol. 41, 103-109.

Academic Career

Assegid Garedew

2006-present Senior Research Fellow at The Wolfson Institute for Biomedical Research, The Cruciform Building, University College London, UK.

2004-2006 Postdoctoral Fellow at Daniel-Swarovski Research Laboratory, Department of General and Transplant Surgery, Innsbruck Medical University, Austria.

2003 PhD in Biology and Biocalorimetry at the Institute of Biology, Free University of Berlin, Germany.

1996 M.Sc. in Biology at the School of Graduate Studies, Faculty of Science, Addis Ababa University, Ethiopia and the Institute for Biophysics, Free University of Berlin, Germany.

1991 B.Sc. in Biology at the Faculty of Science, Addis Ababa University, Ethiopia.

Christoph Schmitt

2008 - present Postdoctoral Research Fellow at The Wolfson Institute for Biomedical Research, UCL.

2004-2008 PhD in Pharmacy at the Department of Pharmacognosy, University of Vienna, Austria.

2004 German license to practice Pharmacy.

2003 Degree in Pharmacy at the University of Heidelberg, Germany.

Funding

Figure 1. J774.A1 murine macrophages stained with the potentiometric dye TMRM and the nuclear stain Hoechst 33342.

Figure 2: A heterogeneous mixture of macrophages after 48 h IFNgamma+LPS treatment: healthy cells with mitochondrial membrane potential (stained red with TMRM), early stage apoptotic cells (stained green with annexin V-FITC and red with TMRM), and late stage apoptotic cells (stained green with annexin V-FITC).