A5064885728- Mitochondrial Function and Pathology
- Adipose Tissue and Metabolism
- Cardiac Ischemia and Reperfusion
- Autophagy in Disease and Therapy
- Sirtuins and Resveratrol in Medicine
- Cardiovascular Function and Risk Factors
- Dietary Effects on Health
- Cancer, Hypoxia, and Metabolism
- ATP Synthase and ATPases Research
- Immune Cell Function and Interaction
- Signaling Pathways in Disease
- Inflammasome and immune disorders
- Diet and metabolism studies
- Cardiac Arrest and Resuscitation
- Anesthesia and Neurotoxicity Research
- Metabolism, Diabetes, and Cancer
- interferon and immune responses
- Biochemical effects in animals
- Endoplasmic Reticulum Stress and Disease
- Cardiac Fibrosis and Remodeling
- Calcium signaling and nucleotide metabolism
- Cardiac electrophysiology and arrhythmias
- Cellular transport and secretion
- Immune Response and Inflammation
- RNA Interference and Gene Delivery
National Heart Lung and Blood Institute
2016-2025
National Institutes of Health
2014-2025
MRC Mitochondrial Biology Unit
2022-2024
University of Cambridge
2023
University of Cape Town
2000-2023
University of Pittsburgh
2020
St Michael's Hospital
2011-2018
Webster University
2012-2014
Johns Hopkins University
2013
Johns Hopkins Bayview Medical Center
2013
Reactive oxygen species (ROS) have an established role in inflammation and host defense, as they kill intracellular bacteria been shown to activate the NLRP3 inflammasome. Here, we find that ROS generated by mitochondrial respiration are important for normal lipopolysaccharide (LPS)-driven production of several proinflammatory cytokines enhanced responsiveness LPS seen cells from patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), autoinflammatory disorder...
Background During the development of heart failure (HF), chief myocardial energy substrate switches from fatty acids to glucose. This metabolic switch, which recapitulates fetal cardiac preferences, is thought maintain aerobic energetic balance. The regulatory mechanisms involved in this response are unknown. Methods and Results To characterize expression genes mitochondrial acid β-oxidation (FAO) failing heart, levels mRNA encoding enzymes that catalyze first third steps FAO cycle were...
Oxidative modification of low-density lipoprotein (LDL) may be atherogenic. We studied the time onset LDL oxidation (lag) in 18 postmenopausal women before and after intraarterial infusion 17 beta-oestradiol, 3 weeks' patch administration 12 these women, 1 month discontinuation 10. The lag increased from baseline acute (from 134 [SD41] to 167 [36] min, p = 0.01) (132 [31] 178 [45] 0.009). After oestradiol, returned baseline. This study shows an antioxidant effect physiological levels which...
Nitrite (NO2−) is an intrinsic signaling molecule that reduced to NO during ischemia and limits apoptosis cytotoxicity at reperfusion in the mammalian heart, liver, brain. Although mechanism of nitrite-mediated cytoprotection unknown, a mediator ischemic preconditioning cell-survival program. Analogous temporally distinct acute delayed cytoprotective phenotypes, we report both (24 h before ischemia) exposure physiological concentrations nitrite, given systemically or orally, potently cardiac...
The “metabolic cocktail” comprising glucose-insulin-potassium administrated at reperfusion reduces infarct size in the vivo rat heart. We propose that insulin is major component mediating this protection and acts via Akt prosurvival signaling. This hypothesis was studied isolated perfused hearts (measuring to area of risk [%]) subjected 35 minutes regional myocardial ischemia 2 hours reperfusion. Insulin administered onset attenuated by ≥45% versus control ( P <0.001). Insulin-mediated...
Acetylation has recently emerged as an important mechanism for controlling a broad array of proteins mediating cellular adaptation to metabolic fuels. is governed, in part, by SIRTs (sirtuins), class III NAD+-dependent deacetylases that regulate lipid and glucose metabolism liver during fasting aging. However, the role acetylation or pathogenic hepatic fuel under nutrient excess unknown. In present study, we isolated acetylated from total proteome observed 193 preferentially mice fed on HFD...
Lysine acetylation is a novel post-translational pathway that regulates the activities of enzymes involved in both fatty acid and glucose metabolism. We examined whether lysine controls heart oxidation high-fat diet (HFD) obese SIRT3 knockout (KO) mice. C57BL/6 mice were placed on either HFD (60% fat) or low-fat (LFD; 4% for 16 18 weeks. Cardiac rates significantly increased vs. LFD (845 ± 76 551 87 nmol/g dry wt min, P < 0.05). Activities enzymes, long-chain acyl-CoA dehydrogenase (LCAD),...
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype poorly defined, pathophysiology unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls conduct deep phenotyping. Among many physical cognitive complaints, one defining feature of was an alteration effort preference, rather than or central fatigue, due dysfunction integrative...
Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels plasma IL-1β lower in fasting compared to fed subjects, while lipid arachidonic acid (AA) elevated. Lipid profiling NLRP3-stimulated mouse macrophages shows enhanced AA production an NLRP3-dependent eicosanoid signature. Inhibition cyclooxygenase by nonsteroidal...
During cardiac hypertrophy, the chief myocardial energy source switches from fatty acid β-oxidation (FAO) to glycolysis—a reversion fetal metabolism. The expression of genes encoding FAO enzymes was delineated in a murine ventricular pressure overload preparation characterize molecular regulatory events involved alteration substrate utilization during hypertrophy. Expression thioesterification, mitochondrial import, and acids coordinately down-regulated after 7 days right (RV) overload....
SIRT3 (sirtuin 3) modulates respiration via the deacetylation of lysine residues in electron transport chain proteins. Whether mitochondrial protein acetylation is controlled by a counter-regulatory program has remained elusive. In present study we identify an essential component this previously undefined acetyltransferase system. We show that GCN5L1 [GCN5 (general control amino acid synthesis 5)-like 1; also known as Bloc1s1] counters and respiratory effects SIRT3. mitochondrial-enriched...
It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links alterations Parkinson disease (PD), and disruption of metabolism found predispose α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase be defective patients early onset PD, regulates systemic metabolism. perturbed levels by exposing Parkin+/+ Parkin–/– mice a high-fat -cholesterol diet (HFD)....
The mitochondrial permeability transition pore (mPTP) opening plays a critical role in mediating cell death during ischemia/reperfusion (I/R) injury. Our previous studies have shown that cysteine 203 of cyclophilin D (CypD), mPTP mediator, undergoes protein S-nitrosylation (SNO). To investigate the activation, we mutated CypD to serine residue (C203S) and determined its effect on opening. Treatment WT mouse embryonic fibroblasts (MEFs) with H(2)O(2) resulted an 50% loss calcein fluorescence,...
The contribution of the Wnt pathway has been extensively characterized in embryogenesis, differentiation, and stem cell biology but not mammalian metabolism. Here, using vivo gain- loss-of-function models, we demonstrate an important role for signaling hepatic In particular, β-catenin, downstream mediator canonical signaling, altered serum glucose concentrations regulated production. β-Catenin also modulated insulin signaling. Furthermore, β-catenin interacted with transcription factor FoxO1...
Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate activation, we investigated whether blunts activation via sirtuin-mediated augmentation integrity.We performed study 19 healthy volunteers. Each subject underwent 24-hour fast then was fed fixed-calorie meal. Blood...
Heme oxygenase (HO)-1 (encoded by Hmox1) catalyzes the oxidative degradation of heme to biliverdin and carbon monoxide. HO-1 is induced during inflammation stress protect tissues from damage. Because intravascular thrombosis forms at sites tissue inflammation, we hypothesized that protects against arterial oxidant stress. To investigate direct function on thrombosis, used photochemical-induced vascular injury in Hmox1-/- Hmox1+/+ mice. mice developed accelerated, occlusive thrombus compared...