Prof. Salvador Moncada
- 020 7679 6789 / s.moncada@ucl.ac.uk

Cardiovascular Research

Lab summary

At physiological concentrations, the gaseous molecule nitric oxide (NO) inhibits the mitochondrial enzyme cytochrome c oxidase in competition with oxygen, and the interplay between the two gases may allow NO to act as a physiological regulator of cell respiration. We are investigating the signalling and bioenergetic consequences of this interaction in physiology and pathophysiology.

We have demonstrated that endogenous NO facilitates the reduction of the mitochondrial electron transport chain and thus favours the release of superoxide anion, which initiates an early signalling stress response. We have also demonstrated that NO is inactivated by cytochrome c oxidase in its oxidised state and that cessation of such inactivation at low [O2] may account for hypoxic vasodilatation.

Nitric oxide-dependent inhibition of respiration leads to a significant redistribution of oxygen, both within and around the cell. This results in a decrease in stabilisation of hypoxia-inducible factor (HIF)-1α at low [O2] and therefore in a decrease in HIF-dependent transcriptional responses.

Inhibition of respiration by NO also results in hyperpolarisation of the mitochondrial membrane. We have shown that this phenomenon, which protects the cells from apoptosis, is dependent on upregulation of glycolysis. This, in turn, is dependent on the activation of a key glycolytic enzyme, phosphofructo-2-kinase. This enzyme is virtually absent in neurons due to its continuous degradation by a proteosome-dependent mechanism, rendering neurons extremely sensitive to energy depletion.

Lab Groups

The group, led by Salvador Moncada (s.moncada@ucl.ac.uk), is interested in cell bioenergetics and their signalling consequences both in physiology and pathophysiology. We are currently concentrating on the following aspects:

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

Nanci Frakich - Cytochrome c oxidase, NO synthase and the soluble guanylyl cyclase

Istvan Kovacs -

Manisha Rajebhosale -

Selected publications

Herrero-Mendez A, Almeida A, Fernández E, et al. (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nature Cell Biol. 11:747-752.

Palacios-Callender M, Hollis V, Mitchison M, et al. (2007) Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilation. Proc. Natl. Acad. Sci. USA 104:18508-18513.

Galkin A, Moncada S. (2007) S-Nitrosation of mitochondrial complex I depends on its structural conformation.  J. Biol. Chem. 282:37448-37453.

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

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Academic Career

Funding

EU, MRC, Wellcome Trust