Michael Duchen
University College London, Cell and Developmental Biology, Faculty Member
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron-specific disorder but increasing evidence... more
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron-specific disorder but increasing evidence indicates non-neuronal cells play a significant role in disease pathogenesis. Although the precise aetiology of ALS remains unclear, mutations in the superoxide dismutase (SOD1) gene are known to account for approximately 20% of familial ALS. We examined the influence of SOD1(G93A) expression in astrocytes on mitochondrial homeostasis in motoneurons in a primary astrocyte : motoneuron co-culture model. SOD1(G93A) expression in astrocytes induced changes in mitochondrial function of both SOD1(G93A) and wild-type motoneurons. In the presence of SOD1(G93A) astrocytes, mitochondrial redox state of both wild-type and SOD1(G93A) motoneurons was more reduced and mitochondrial membrane potential decreased. While intra-mitochondrial calcium levels [Ca(2+)](m) were elevated in SOD1(G93A) motoneurons, changes in mitochondrial function did not correlate with [Ca(2+)](m). Thus, expression of SOD1(G93A) in astrocytes directly alters mitochondrial function even in embryonic motoneurons, irrespective of genotype. These early deficits in mitochondrial function induced by surrounding astrocytes may increase the vulnerability of motoneurons to other neurotoxic mechanisms involved in ALS pathogenesis.
Research Interests: Neuroscience, Biology, Neurochemistry, Calcium, Motor neuron, and 15 moreImmunohistochemistry, Mitochondria, Medicine, Gene expression, Amyotrophic Lateral Sclerosis, Humans, Mice, Animals, Astrocyte, Astrocytes, Glial Fibrillary Acidic Protein, Cell Survival, Mitochondrion, Motor Neurons, and coculture techniques
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Mitochondria play a central role in cell biology not only as producers of ATP, but also in the sequestration of Ca(2+) and the generation of free radicals. They are also repositories of several proteins which regulate apoptosis.... more
Mitochondria play a central role in cell biology not only as producers of ATP, but also in the sequestration of Ca(2+) and the generation of free radicals. They are also repositories of several proteins which regulate apoptosis. Perturbations in the normal functions of mitochondria will inevitably disturb cell function, may sensitise cells to neurotoxic insults and may initiate cell death. Neuronal Ca(2+) overload, such as follows excessive stimulation of Ca(2+) permeant excitatory amino acid receptors, can cause cell death. Recent evidence suggests that the accumulation of Ca(2+) into mitochondria during episodes of cellular Ca(2+) overload initiates a cascade of events that culminate in cell death. Cell death appears to require not only mitochondrial Ca(2+) overload, but rather a combination of raised intramitochondrial Ca(2+) concentration with increased production of nitric oxide and possibly other oxyradical species. Cell death may proceed through either necrotic or apoptotic mechanisms, depending on the rate of consumption and depletion of ATP. Evidence is also accumulating to suggest that more subtle alterations in mitochondrial function may serve as predisposing factors in the pathogenesis of a number of neurodegenerative disorders.
Research Interests: Free Radicals, Biology, Calcium, Cell Biology, Mitochondria, and 15 moreApoptosis, Medicine, Neurodegenerative Diseases, Free Radical, Glutamate, Humans, Nitric oxide, Animals, Cell, Cell Death, Neurodegenerative Disease, Mitochondrion, Neurodegenerative disorder, Pharmacology and pharmaceutical sciences, and Motor neuron disease
Research Interests: Biophysics, Kinetics, Biology, Calcium, Cell Biology, and 15 moreFluorescent Dyes and Reagents, Medicine, Biological Sciences, Cerebral Cortex, Animals, Endoplasmic Reticulum, Astrocyte, Calcium Signaling, Fluorescence Imaging, Astrocytes, Membrane Potential, Adenosine Triphosphate, Depolarization, fluorescent dyes, and Medical and Health Sciences
Research Interests: Biology, Cell Biology, Mitochondria, Medicine, Bioenergetics, and 15 moreFree Radical, Biological Sciences, Mitochondrial DNA, Humans, Nitric oxide, Animals, Cell Death, Mitochondrial disease, Cell Signalling, Fluorescence Imaging, Genome, MITOCHONDRIAL BIOGENESIS, Neurodegenerative Disease, Mitochondrion, and Medical and Health Sciences
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The mitochondrial F1Fo‐ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and... more
The mitochondrial F1Fo‐ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age‐related diseases. In a recent study, Acin‐Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)‐epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.
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Mitochondrial heteroplasmy is the presence of more than one type of mitochondrial DNA within cells and tissues: notably mtDNA with a mutation and wild-type mtDNA. Mitochondria generate the energy to sustain cell viability and serve as a... more
Mitochondrial heteroplasmy is the presence of more than one type of mitochondrial DNA within cells and tissues: notably mtDNA with a mutation and wild-type mtDNA. Mitochondria generate the energy to sustain cell viability and serve as a hub for cell signalling. Their own genome (mtDNA) encodes genes critical for oxidative phosphorylation. Mutations of mtDNA cause major disease and disability with a wide range of presentations and severity. We review here an emerging body of data suggesting that changes in cell metabolism and signalling pathways in response to the presence of mtDNAmutations play a key role in shaping disease presentation and progression. Understanding the impact of mtDNAmutations on cellular energy homeostasis and signalling pathways seems fundamental to identify novel therapeutic interventions with the potential to improve the prognosis for patients with primary mitochondrial disease.
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Objectives: To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis. Design: In vivo and ex vivo controlled experimental studies. Setting: University... more
Objectives: To investigate the relationship between prognosis, changes in mitochondrial calcium uptake, and bioenergetic status in the heart during sepsis. Design: In vivo and ex vivo controlled experimental studies. Setting: University research laboratory. Subjects: Male adult Wistar rats. Interventions: Sepsis was induced by intraperitoneal injection of fecal slurry. Sham-operated animals served as controls. Confocal microscopy was used to study functional and bioenergetic parameters in cardiomyocytes isolated after 24-hour sepsis. Electron microscopy was used to characterize structural changes in mitochondria and sarcoplasmic reticulum. The functional response to dobutamine was assessed in vivo by echocardiography. Measurements and Main Results: Peak aortic blood flow velocity measured at 24 hours was a good discriminator for 72-hour survival (area under the receiver operator characteristic, 0.84 ± 0.1; p = 0.03) and was used in ex vivo experiments at 24 hours to identify septic ...
Research Interests: Nursing, Calcium, Mitochondria, Medicine, Bioenergetics, and 15 moreCritical Care Medicine, Echocardiography, Animals, Male, Clinical Sciences, In Vivo, Rats, Calcium Metabolism, NAD, Adenosine Triphosphate, Sarcoplasmic reticulum, Mitochondrion, NAD metabolism, Nicotinamide adenine dinucleotide, and ex vivo
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We have applied reductionist methods to the investigation of carotid body function, isolating the component cells of the structure in order to define their properties in greater detail than previously possible. In particular, we have... more
We have applied reductionist methods to the investigation of carotid body function, isolating the component cells of the structure in order to define their properties in greater detail than previously possible. In particular, we have focused on the type I (or glomus) cell, because of the generally held view that the transduction process resides in this cell. The cellular processes which underlie transduction remain obscure. According to one view, following a hypoxic stimulus, transmitters released from type I cells will excite the terminations of axons of sensory neurons, which have their cell bodies in the petrosal ganglion. Thus, changes in stimulus intensity are signalled to the CNS via the glossopharyngeal nerve.
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Research Interests: Chemistry, Calcium, Mitochondria, Confocal Microscopy, Medicine, and 15 moreBrain, Humans, Mice, Animals, Cell Fractionation, Catalase, Electron Transport, Hydrogen Peroxide, HeLa cells, Benzimidazoles, Human Fibroblasts, Biochemistry and cell biology, fibroblasts, Mitochondrial Bioenergetics, and Mitochondrial ROS
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An increasing volume of data suggests that changes in cellular metabolism have a major impact on the health of tissues and organs, including in the auditory system where metabolic alterations are implicated in both age-related and... more
An increasing volume of data suggests that changes in cellular metabolism have a major impact on the health of tissues and organs, including in the auditory system where metabolic alterations are implicated in both age-related and noise-induced hearing loss. However, the difficulty of access and the complex cyto-architecture of the organ of Corti has made interrogating the individual metabolic states of the diverse cell types present a major challenge. Multiphoton fluorescence lifetime imaging microscopy (FLIM) allows label-free measurements of the biochemical status of the intrinsically fluorescent metabolic cofactors NADH and NADPH with subcellular spatial resolution. However, the interpretation of NAD(P)H FLIM measurements in terms of the metabolic state of the sample are not completely understood. We have used this technique to explore changes in metabolism associated with hearing onset and with acquired (age-related and noise-induced) hearing loss. We show that these conditions...
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Research Interests: Multiple sclerosis, Biology, Biological Chemistry, Neurodegeneration, Medicine, and 15 moreBiological Sciences, Humans, Liver, Mutation, Cerebral Cortex, Animals, Male, Neurons, CHEMICAL SCIENCES, Mitochondrial Permeability Transition Pore, Cell Proliferation, Neuroprotective Agents, Mitochondrion, Medical and Health Sciences, and MPTP
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Research Interests: Biology, Calcium, Cell Biology, Mitochondria, Neurodegeneration, and 15 moreMedicine, Ion Channels, Glutamate, Animals, Cell Death, Glutathione, Astrocyte, Astrocytes, NADPH oxidase, Mitochondrial dysfunction, Metabolic pathway, Depolarization, Mitochondrion, Complex I, and Medical and Health Sciences
Mitochondrial dysfunction plays a role in the pathogenesis of a wide range of diseases that involve disordered cellular fuel metabolism and survival/death pathways, including neurodegenerative diseases, cancer and diabetes. Cytokine,... more
Mitochondrial dysfunction plays a role in the pathogenesis of a wide range of diseases that involve disordered cellular fuel metabolism and survival/death pathways, including neurodegenerative diseases, cancer and diabetes. Cytokine, virus recognition and cellular stress pathways converging on mitochondria cause apoptotic and/or necrotic cell death of beta-cells in type-1 diabetes. Moreover, since mitochondria generate crucial metabolic signals for glucose stimulated insulin secretion (GSIS), mitochondrial dysfunction underlies both the functional derangement of GSIS and (over-nutrition) stress-induced apoptotic/necrotic beta-cell death, hallmarks of type-2 diabetes. The apparently distinct mechanisms governing beta-cell life/death decisions during the development of diabetes provide a remarkable example where remote metabolic, immune and stress signalling meet with mitochondria mediated apoptotic/necrotic death pathways to determine the fate of the beta-cell. We summarize the main findings supporting such a pivotal role of mitochondria in beta-cell death in the context of current trends in diabetes research.
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Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca2+ acts... more
Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca2+ acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca2+ stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca2+-regulated mitochondrial carriers, whereas an increase in matrix Ca2+ stimulates the citric acid cycle and ATP synthase. The aspartate–glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate–aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca2+ and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K+-depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca2+ influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca2+]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca2+ signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca2+ is increased and mitochondria fragmented. Thus, the fine tuning of Ca2+ signals plays a key role in shaping mitochondrial bioenergetics.
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Research Interests: Cancer, Biology, Calcium, Cell Biology, Mitochondria, and 15 moreMedicine, Biological Sciences, Cercopithecus aethiops, Cell line, Cancer Therapy, Mice, Animals, Cell Death, Cancer Cell, Gene Expression Analysis, Calcium Binding Proteins, Cell Survival, Adenosine Triphosphate, Adenosine Diphosphate, and Medical and Health Sciences
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Research Interests: Biology, Cell Biology, Medicine, Protein Structure and Function, In Vitro, and 15 moreATPase, Animals, Heart, ATP synthase, Proteins, Medical Physiology, Respiration, Rats, Oxidative phosphorylation, Biochemistry and cell biology, Gene Expression Regulation, Adenosine Triphosphate, Mitochondrion, cell metabolism, and Medical biochemistry and metabolomics
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ABSTRACT Ischemic stroke is a major cause of death and disability urgently requiring novel therapeutic approaches. Deprivation of oxygen Ischemic stroke is a major cause of death and disability urgently requiring novel therapeutic... more
ABSTRACT Ischemic stroke is a major cause of death and disability urgently requiring novel therapeutic approaches. Deprivation of oxygen Ischemic stroke is a major cause of death and disability urgently requiring novel therapeutic approaches. Deprivation of oxygen and respiratory substrate during an ischemic episode has its most immediate impact on mitochondria, the body’s primary oxygen and respiratory substrate during an ischemic episode has its most immediate impact on mitochondria, the body’s primary oxygen consumers. Mitochondrial function is in turn critically dependent on a range of carriers and channels, most of which remain consumers. Mitochondrial function is in turn critically dependent on a range of carriers and channels, most of which remain inadequately understood at the genetic and molecular level. As mitochondrial channels are involved in energy production, calcium inadequately understood at the genetic and molecular level. As mitochondrial channels are involved in energy production, calcium handling, generation of reactive oxygen species (ROS) and cell-death related signaling, it is evident that increased understanding handling, generation of reactive oxygen species (ROS) and cell-death related signaling, it is evident that increased understanding of these processes and their regulation will help the search for novel rational approaches to therapy. of these processes and their regulation will help the search for novel rational approaches to therapy.
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... Montero and colleagues [28] showed that, while collapse of Δψm prevents mitochondrial Ca2 uptake, collapse of Δψm after the accumulation of ... We also thank Remi Dumollard, Jake Jacobson, and Laura Canevari for their invaluable... more
... Montero and colleagues [28] showed that, while collapse of Δψm prevents mitochondrial Ca2 uptake, collapse of Δψm after the accumulation of ... We also thank Remi Dumollard, Jake Jacobson, and Laura Canevari for their invaluable discussion and comments on the manuscript ...
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NADH and NADPH are redox cofactors, primarily involved in catabolic and anabolic metabolic processes respectively. In addition, NADPH plays an important role in cellular antioxidant defence. In live cells and tissues, the intensity of... more
NADH and NADPH are redox cofactors, primarily involved in catabolic and anabolic metabolic processes respectively. In addition, NADPH plays an important role in cellular antioxidant defence. In live cells and tissues, the intensity of their spectrally-identical autofluorescence, termed NAD(P)H, can be used to probe the mitochondrial redox state, while their distinct enzyme-binding characteristics can be used to separate their relative contributions to the total NAD(P)H intensity using fluorescence lifetime imaging microscopy (FLIM). These protocols allow differences in metabolism to be detected between cell types and altered physiological and pathological states.