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The Seminar series will resume in September. Please check back for details. 

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Home | Research | People | Publications | Lab History | Odra Noel Images

Current work in the lab includes:

1 Imaging mechanisms of ischaemia and reperfusion injury in intact organ systems

Cellular responses to hypoxia/anoxia and reoxygenation – sources and targets of oxidative stress, mechanisms of cell injury and mechanisms of cellular protection, studied using multiphoton confocal microscopy in intact isolated perfused organs – heart and kidney. Collaborations with Sean Davidson (post doctoral research fellow, Hatter Institute) and Andrew Hall (Clinical Lecturer in Nephrology, RFH)
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2 Muscle

Relationships between mitochondrial function and calcium signalling in congenital muscle diseases (collaborations with Francesco Muntoni, ICH and Mike Hanna, IoN).
Roles of mitochondrial biogenesis and autophagy in muscle hypertrophy and atrophy. people: Iulia Oprea (post doc) Katherine Heath and Neta Baruch (PhD students)
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3 Neuronal

Parkinson’s Disease: Mitochondrial quality control and bioenergetic function in relation to Parkinsons’ Disease, including interactions between mitochondria and lysosomal signalling as a collaboration with Sandip Patel (CDB). Project as part of the WT/MRC strategic award in PD. People: Laura Osellame and Juan Carlos Corona (post docs)
Exploring mechanisms of neuronal death in Alzheimer’s Disease, using the retina and/or hippocampal explant cultures from AD transgenic mouse models to explore changes in mitochondrial function and cell signalling in simple neuronal networks. Collaborations with Francesca Cordeiro at the IoO and Frances Edwards.
Also using the retina whole mount preparation with multiphoton imaging to study mitochondrial contributions to neuronal degeneration in retinitis pigmentosa (collaboration with Mike Cheetham at IoO)
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4 Roles of the mitochondrial protein IF1 in cell physiology

To include roles of IF1 in the heart, neurons and pancreatic beta cells in regulation of mitochondrial structure and function and in regulating cell death pathways. To understand the roles and impact of the mitochondrial ATPase in driving cell fate. Coupled with search for small molecule inhibitors of the ATPase. People: Nadeene Parker (post doc), Rachel Tan and Fabrice Ivanes (PhD students). Collaboration with Michelangelo Campanella, RVC, Jon Wilden (Chemistry) and Vincent Gray (PhD student).
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5 Applications of Fluorescence Lifetime imaging (FLIM)

Project to explore the interpretation of fluorescence lifetime signals, to unravel the compartmentalisation of NADH in cells in different metabolic states and specifically to understand the metabolic basis for changes in NADH lifetimes in cancer as a diagnostic and predictive tool. Thomas Blacker (CoMPLEX PhD student, collaboration with Angus Bain, laser Physics)
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Some Background

Mitochondria and calcium signaling 

Mitochondria take up calcium avidly. We have for some time been interested in the physiological significance of this pathway. Over recent years it has become clear that all physiological calcium signaling in all cells – associated with muscle contraction, secretion of neurotransmitters or hormones, cell motility and so on – is accompanied by the transfer of calcium into the mitochondrial matrix.


This has consequences:

i) for mitochondrial function, causing a small depolarisation of the mitochondrial potential, upregulation of the citric acid cycle, and of the ATP synthase. This increases oxidative phosphorylation and provides and elegant and simple mechanism to couple the increased energy demand (that is an inevitable accompaniment to any events associated with calcium signals) with increased energy supply.

ii) for cell signaling - mitochondrial uptake may act as a fixed buffer thereby regulating the spatio-temporal properties of calcium signals in cells. As the downstream effects of calcium signals are critically dependent on the fine tuning of the spatial and temporal features of the calcium signal, this may have a profound impact on cell function. 

Movies: these show firstly the propagation of a calcium wave induced by ATP addition to an astrocyte in culture. The wave propagates at about 20microns per second and slows as it moves across the cell. In the second movie, the mitochondria were depolarised (and so cannot accumulate calcium) and the wave moves faster (about 35microns per second) and maintains speed across the cell. Thus, mitochondrial calcium uptake acts as a fixed spatial calcium buffering system.

ATP induced calcium wave in astrocyte
atp induced calcium wave is accelerated after loss of mitochondrial calcium uptake

iii) for cell fate: for some years we have been studying the role of the large conductance pore (widely known as the permeability transition pore, mPTP) that opens in the mitochondrial inner membrane under precisely those conditions that prevail during reperfusion of ischaemic myocardium. Opening of such a pore disrupts the chemiosmotic basis for oxidative phosphorylation, and makes the generation of ATP required for recovery impossible. Pore opening has also been linked to the initiation of apoptosis. We have sought evidence for the expression of this phenomenon in isolated cells including cardiomyocytes, astrocytes and neurons, and have evidence for pore opening on reperfusion after anoxia, in response to oxidative stress, which may be generated in a variety of ways and following glutamate toxicity in neurons. The pore is closed by cyclosporin A, which also serves to protect myocytes from reperfusion injury and neurons from glutamate toxicity. Recent evidence suggests that a number of cardioprotective mechanisms involve an alteration in the probability of mPTP opening

ATP movie: Astrocytes loaded with rhod-2 and stimulated with ATP to mobilise intracellular calcium stores. Mitochondrial calcium accumulation is clear after the stimulus.

see: Szabadkai G, Duchen MR. Mitochondria: the hub of cellular Ca2+ signaling. Physiology (Bethesda). 2008 Apr;23:84-94.

Page last modified on 21 oct 10 11:59