Introduction

Research Groups

Select Research Group Head Prof. Sir Tom Blundell Prof. Kevin Brindle Dr Bill Broadhurst Dr Guy Brown Dr Mark Carrington Prof. Paul Dupree Prof. Gerard Evan - Head of Dept Prof. Richard Farndale Dr Giorgio Favrin Dr Jenny Gallop Dr Nick Gay Dr Andrew Grace Dr Jules Griffin Dr Brian Hendrich Dr Andrew Hesketh Dr Robin Hesketh Dr Matt Higgins Dr Florian Hollfelder Dr Hee-Jeon Hong Prof. Chris Howe Dr Marko Hyvonen Prof. Steve Jackson Dr Tony Jackson Prof. Richard Jackson Prof. Ernest Laue Prof. Peter Leadlay Dr Kathryn Lilley Dr Karen Lipkow Dr Rick Livesey Prof. Ben Luisi Dr Sarah Lummis Dr Juan Mata Dr John McCafferty Prof. Jim Metcalfe Dr Masanori Mishima Dr Eric Miska Dr Tom Monie Dr Helen Mott Dr Natasha Murzina Dr Daniel Nietlispach Dr Darerca Owen Prof. Steve Oliver Dr Luca Pellegrini Dr Markus Ralser Dr Nick Robinson Prof. George Salmond Dr Deirdre Scadden Dr José Silva Prof. Austin Smith Prof. Chris Smith Dr Nancy Standart Prof. Dame Jean Thomas Dr Aviva Tolkovsky Dr Martin Welch Dr Joyce Wong Dr Nianshu Zhang

Service & Research Support Facilities

Select by Subject or Manager DNA Sequencing Facility . . . . . Mr John Lester _______________________________ Quantitative Proteomics . . . . . Dr Kathryn Lilley _______________________________ Proteomics Core Services . . . . . Dr Mike Deery _______________________________ Protein & Nucleic Acid Chemistry . . . . . Dr Len Packman _______________________________ Metabolomics . . . . . Dr Jules Griffin _______________________________ Baculovirus Facility . . . . . Dr Darerca Owen _______________________________ Biophysics Facility . . . . . Dr Katherine Stott _______________________________ Crystallographic X-ray Facility . . . . . Dr Dima Chirgadze _______________________________ NMR spectroscopy . . . . . Dr Daniel Nietlispach _______________________________ Fermentation Facility . . . . . Dr Nianshu Zhang _______________________________ Bioinformatics & Computational Biology Services . . . . . Dr Jenny Barna _______________________________ Computer & IT Support . . . . . Dr Erik Timmers _______________________________

Past members last known active weblink

Select past member of Department Dr Stephen Bell Prof. Jonathan Blackburn Dr David Brown Dr Pak-Lee Chau Dr Hal Dixon (deceased) Dr Jessica Downs Prof. David Ellar Dr Paul Kemp Dr Simon Lovell Dr Kenji Mizuguchi Dr Massimo Paoli Prof. Richard Perham Dr Peter Reynolds Dr Philip Rubery Dr Gerry Smith Dr Margaret Sunde Prof. Jamie Vandenberg Dr Kira Weissman

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Cambridge Neuroscience

Nitric Oxide, Mitochondria and Cell Death

Research Groupings: Structural and molecular cell biology | Developmental and regenerative biology and medicine

We are interested in the roles of nitric oxide (NO), reactive oxygen species (ROS) and mitochondria in cell physiology and pathology. We generally use biochemical and cell biology approaches to investigate molecular mechanisms in physiology and disease.

We have shown that NO inhibits mitochondrial respiration by two mechanisms: (i) reversible inhibition of cytochrome c oxidase in competition with oxygen, and (ii) inactivation of complex I by S-nitrosothiols and peroxynitrite. The latter two reactive nitrogen species (RNS) also activate the mitochondrial permeability transition pore and cause cytochrome c release. These and other interactions lead to increased ROS and RNS production by mitochondria and cells. We have been characterising the roles of all these interactions in NO-induced cell death and cytostasis.

Healthy cerebellar granule neurons in culture, showing neuronal cell bodies and extensive neuronal processes	The same culture 48 hours after inflammatory activation, showing loss of neurons and processes, but microglia are large and activated

Brain glial cells (astrocytes and microglia) become inflamed and express inducible NO synthase (iNOS) in stroke, infection, neurodegeneration and aging. We find that inflamed glia kill co-cultured neurons via release of NO from iNOS. We have been elucidating the mechanisms involved in this inflammatory neurodegeneration, and means of preventing it.

Blood vessels become inflamed during atheroschlerosis and sepsis. We have shown that iNOS expression in inflamed aorta inhibits mitochondrial respiration in competition with oxygen, and sensitises the vessel wall to hypoxic damage.

Heart attacks and heart failure damage the heart via ischaemia (reduced blood flow). We have found that ischaemia of the heart causes very rapid mitochondrial damage and apoptosis, via activation of mitochondrial permeability transition, and we are investigating the mechanisms involved.

We are interested generally in how mitochondria within cells regulate cell functions and cell death. For example, we have been investigating how mitochondrial respiration and redox state affects cell proliferation and cell death.

Lab members
Richard Brown, Michael Fricker, Tamara Hornick, Jonas Neher

References

1. Jekabsone A, Mander PK, Tickler A, Sharpe M, Brown GC. (2006) Fibrillar beta-amyloid peptide Aβ_1-40 activates microglial proliferation via stimulating TNF-alpha release and H₂O₂ derived from NADPH oxidase: a cell culture study. J Neuroinflammation. 3:24.
2. Jekabsone, A., Nehrer, J., Borutaite, V. & Brown, G. C. (2007) Nitric oxide from neuronal nitric oxide synthase sensitises neurons to hypoxia-induced death via competitive inhibition of cytochrome oxidase. J. Neurochem. 103, 346-356.
3. Brown GC, Borutaite V. (2007) Mitochondrial regulation of caspase activation by cytochrome oxidase and tetramethylphenylenediamine (TMPD) via cytosolic cytochrome C redox state. J Biol Chem. 282, 31124-30.