A5031855944- Mitochondrial Function and Pathology
- Cardiac Ischemia and Reperfusion
- ATP Synthase and ATPases Research
- Adipose Tissue and Metabolism
- Cardiac Arrest and Resuscitation
- Peptidase Inhibition and Analysis
- Metabolism and Genetic Disorders
- Cancer, Hypoxia, and Metabolism
- Advanced biosensing and bioanalysis techniques
- Nitric Oxide and Endothelin Effects
- Muscle metabolism and nutrition
- Trace Elements in Health
- Colorectal Cancer Treatments and Studies
- Sulfur Compounds in Biology
- Alzheimer's disease research and treatments
- Endoplasmic Reticulum Stress and Disease
- Metabolomics and Mass Spectrometry Studies
- thermodynamics and calorimetric analyses
- Exercise and Physiological Responses
- Pharmaceutical Practices and Patient Outcomes
- Opioid Use Disorder Treatment
- Toxoplasma gondii Research Studies
- Chemical and Physical Studies
- Neurological Disorders and Treatments
- Viral Infections and Immunology Research
Dana-Farber Cancer Institute
2023-2025
Harvard University
2023-2025
MRC Mitochondrial Biology Unit
2018-2022
University of Cambridge
2018-2022
Medical Research Council
2019-2022
Develco Pharma (Switzerland)
2020
University of Freiburg
2009-2018
Institute of Medical Microbiology and Hygiene
2015
University Medical Center Freiburg
2015
The University of Texas Medical Branch at Galveston
1983
Abstract Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding P25L substitution in ND6 subunit of I. The cryo-EM structure revealed subtle structural changes facilitate rapid conversion “deactive” state, usually formed only after prolonged inactivity. Despite its tendency adopt mutant fully active NADH oxidation,...
The Tricarboxylic Acid (TCA) Cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, redox homeostasis. Despite decades of research, a comprehensive investigation into consequences TCA dysfunction remains elusive. Here, we targeted two enzymes, fumarate hydratase (FH) succinate dehydrogenase (SDH), combined metabolomics, transcriptomics, proteomics analyses to fully appraise inhibition (TCAi)...
Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular apoptosis induction selectively tumor through oxygen-mediated inactivation of protective catalase subsequent reactivation intercellular ROS-mediated signaling the HOCl NO/peroxynitrite pathway. Singlet by photofrin alone was, however, not sufficient for optimal direct catalase, but needed to trigger cell-derived...
Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim our study was to determine whether beneficial effects hypothermia may be due decreasing mitochondria-mediated mechanisms damage that contribute pathophysiology ischemia/reperfusion injury. New Zealand male rabbits were submitted 30 min with (32 °C) by total liquid ventilation (TLV). applied during alone (TLV group), and reperfusion (TLV-IR group) normothermia...
Coenzyme Q (CoQ) is an essential cofactor, primarily found in the mitochondrial inner membrane where it functions as electron carrier respiratory chain, and a lipophilic antioxidant. The redox state of CoQ pool ratio its oxidised (ubiquinone) reduced (ubiquinol) forms, key indicator bioenergetic antioxidant status. However, role vivo poorly understood, because determining value technically challenging due to changes during isolation, extraction analysis. To address these problems, we have...
Mammalian complex I can adopt catalytically active (A-) or deactive (D-) states. A defining feature of the reversible transition between these two defined states is thought to be exposure ND3 subunit Cys39 residue in D-state and its occlusion A-state. As catalytic A/D important health disease, we set out quantify it by measuring using isotopic labeling mass spectrometry, parallel with NADH/CoQ oxidoreductase activity. To our surprise, found significant during Furthermore, this activity was...
Respiratory complex I is an essential metabolic enzyme that uses the energy from NADH oxidation and ubiquinone reduction to translocate protons across transducing membrane generate proton motive force for ATP synthesis. Under specific conditions, can also catalyze reverse reaction, Δp-linked of ubiquinol reduce NAD+ (or O2), known as electron transfer (RET). Oxidative damage by reactive oxygen species generated during RET underpins ischemia reperfusion injury, but relies on several...
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....
ABSTRACT Borna disease virus (BDV) is a neurotropic member of the order Mononegavirales with noncytolytic replication and obligatory persistence in cultured cells animals. Here we show that accessory protein X BDV represents first mitochondrion-localized an RNA inhibits rather than promotes apoptosis induction. Rat C6 astroglioma persistently infected wild-type were significantly more resistant to death receptor-dependent -independent apoptotic stimuli uninfected or mutant expressing reduced...
Reactive oxygen species (ROS) have an equivocal role in myocardial ischaemia reperfusion injury. Within the cardiomyocyte, mitochondria are both a major source and target of ROS. We evaluate effects selective, dose-dependent increase mitochondrial ROS levels on cardiac physiology using mitochondria-targeted redox cycler MitoParaquat (MitoPQ). Low decrease susceptibility neonatal rat ventricular myocytes (NRVMs) to anoxia/reoxygenation injury also cause profound protection vivo mouse model...
Abstract Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT have been linked age-related disorders, including neurodegenerative and cardiovascular diseases, while supplementation protective broad range of disease aging models mice. Despite these promising data, the direct physiologically relevant molecular target has remained elusive. Here we use systematic approach identify how mitochondria remodel their metabolome...
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...
Zinc is an essential micronutrient that regulates a wide range of physiological processes, principally through Zn2+ binding to protein cysteine residues. Despite being critical for modulation function, the vast majority human proteome sites subject regulation by remain undefined. Here we develop ZnCPT, comprehensive and quantitative mapping zinc-regulated proteome. We define 4807 cysteines, uncovering families across major domains biology are either constitutive or inducible modification...
Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation function, the sites in majority human proteome are subject remain undefined. Here, we develop ZnCPT, deep and quantitative mapping zinc-binding proteome. We define 6,173 cysteines, uncovering families across major domains biology constitutive or inducible binding. ZnCPT enables systematic discovery...
Approximately 70% of mitochondrial precursor proteins are imported from the cytosol via N-terminal presequences, which cleaved upon exposure to processing protease MPP in matrix. Cleaved presequence peptides then need be efficiently degraded, and impairment this clearance step, for example, by amyloid β peptides, causes feedback inhibition MPP, leading ultimately accumulation immature within mitochondria. Degradation is performed Cym1 yeast its homologue, PreP, humans. Here we identify novel...