A5022297024- Mitochondrial Function and Pathology
- Adipose Tissue and Metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Cardiac Ischemia and Reperfusion
- Sulfur Compounds in Biology
- Cardiac Arrest and Resuscitation
- Cardiac electrophysiology and arrhythmias
- ATP Synthase and ATPases Research
- Heme Oxygenase-1 and Carbon Monoxide
- Cancer, Hypoxia, and Metabolism
- Neuroscience of respiration and sleep
- Pancreatic function and diabetes
- Immune Response and Inflammation
- Metabolomics and Mass Spectrometry Studies
- Metabolism, Diabetes, and Cancer
- Immune cells in cancer
- Metabolism and Genetic Disorders
- Nitric Oxide and Endothelin Effects
MRC Mitochondrial Biology Unit
2018-2024
University of Cambridge
2018-2024
Addenbrooke's Hospital
2021
Wellcome Trust
2018
Background: Inhibiting SDH (succinate dehydrogenase), with the competitive inhibitor malonate, has shown promise in ameliorating ischemia/reperfusion injury. However, key for translation to clinic is understanding mechanism of malonate entry into cells enable inhibition SDH, its mitochondrial target, as itself poorly permeates cellular membranes. The possibility selectively entering at-risk heart tissue on reperfusion, however, remains unexplored. Methods: C57BL/6J mice, C2C12 and H9c2...
Mitochondria-targeted H2S donors are thought to protect against acute ischemia-reperfusion (IR) injury by releasing that decreases oxidative damage. However, the rate of release current is too slow be effective upon administration following reperfusion. To overcome this limitation here we develop a mitochondria-targeted agent, MitoPerSulf very rapidly releases within mitochondria. quickly taken up mitochondria, where it reacts with endogenous thiols generate persulfide intermediate H2S....
The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production ATP, signaling, and fate. It is regulated by ATPase inhibitory factor 1 (IF1), which highly abundant in neurons. Herein, we ablated or overexpressed IF1 mouse neurons to show that dose defines fraction active/inactive enzyme vivo, thereby function reactive oxygen species (mtROS). Transcriptomic, proteomic, metabolomic analyses indicate regulates metabolism, synaptic function, cognition....
Cell models of cardiac ischemia-reperfusion (IR) injury are essential to facilitate understanding, but current monolayer cell poorly replicate the in vivo IR that occurs within a three-dimensional tissue. Here we show this is for two reasons: residual oxygen present many cellular hypoxia sustains mitochondrial oxidative phosphorylation; and loss lactate from cells into incubation medium during ischemia enables sustain glycolysis. To overcome these limitations, incubated isolated adult mouse...
Cells naturally produce mitochondrial reactive oxygen species (mROS), but the in vivo pathophysiological significance has long remained controversial. Within brain, astrocyte-derived mROS physiologically regulate behaviour and are produced at one order of magnitude faster than neurons. However, whether neuronal abundance differentially impacts on is unknown. To address this, we engineered genetically modified mice to down modulate levels neurons vivo. Whilst no alterations motor coordination...
ABSTRACT Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark several chronic neurological diseases, including multiple sclerosis (MS) 1 . Distinct metabolic and mitochondrial features guide the diverse functional states 2 However, how these act to perpetuate neuroinflammation currently unknown. Using multiomics approach, we identified new molecular signature that perpetuates through complex II (CII) I (CI) activity driving reverse electron transport (RET)...
The compartmentation and distribution of metabolites between mitochondria the rest cell is a key parameter signalling pathology. Here, we have developed rapid fractionation procedure that enables us to take mouse heart liver from in vivo within ~ 30 s stabilise cytosol by cooling, homogenisation dilution. This followed centrifugation through an oil layer separate mitochondrial cytosolic fractions for subsequent metabolic analysis. Using this revealed will enable assessment during range situations .