Cardiovascular Research

Dr Sergio Colombo

Mitochondria - Nitric oxide signalling pathway: the downstream role of AMPK

Our laboratory has characterized in detail the interaction between NO and cytochrome c oxidase and I am currently studying the signalling consequences of this interaction. Since the competition between NO and O2 in the mitochondria becomes relevant at low O2 concentrations, we have shown that when human vascular endothelial cells are exposed to physiological levels of O2 (i.e. 3%), the AMP-activated protein kinase alpha1 is activated by a mechanism independent of energy changes, but dependent on mitochondrial reactive oxygen species (mtROS). One of our current hypotheses is that AMPK alpha1, activated by mtROS, participates in the orchestration of cellular defence mechanisms, mainly by modulating gene expression.

We have generated several genetic models (eg eNOS-/- and AMPK alpha1 -/-) to study the downstream consequences of this signalling pathway, exploiting the benefits of reverse genetics. A second core area of our research is to investigate the molecular mechanisms involved in the transduction of the mtROS signal in the activation of this pathway.

Selected publications

1. Sergio L Colombo and Salvador Moncada (2009) – “AMPKalpha1 regulates the antioxidant defence of the vascular endothelial cells”. Biochem J Signal. 421:163-169.

2. Quintero M, Colombo S, Godfrey A and Moncada S (2006) Mitochondria as signaling organelles in the
vascular endothelium. Proc Natl Acad Sci U S A 103: 5379-5384.

3. Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S. (2004) Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci U S A 101:7630-7635.

Academic Career

2004-present - Wolfson Inst. Biomedical Research, University College London, London - UK. Senior Research Postdoc.

2002-2004 - GlaxoSmithKline, CEDD of Neurology, Harlow - UK. Marie Curie EU Postdoc.

1998-2002 - Biological Sciences Dept, Louisiana State University. Baton Rouge – USA. Postdoc

1993-1998 - National University of Rosario, CEFOBI Rosario, Argentina. PhD.

Funding

Figure 1:
Proposed model of the NO/mitochondria signalling pathway.