The first completion of WPs from this ERC grant involves: ‘Non-canonical transamination metabolism of glutamine sustains efferocytosis by coupling oxidative phosphorylation to oxidative stress buffering’. This manuscript has been published by Merlin et al., in Nature metabolism in 2021. Briefly, tissue macrophages rely on tightly integrated metabolic rewiring to maintain tissue integrity and continuously clear neighboring cells that turnover during homeostasis and disease. Glutaminase (Gls1) converts glutamine to glutamate to fuel anabolic reactions and support cellular redox balance. Here, we identify a critical role for Gls1 in promoting apoptotic cell (AC) clearance by macrophages (efferocytosis) after interleukin-4 (IL-4) stimulation or upon multiple rounds of AC exposure, which are two physiologic paradigms. Mice selectively lacking macrophage glutaminolysis showed defective efferocytosis in vivo and significant pathologic consequences in atherosclerotic lesions of fat-fed ApoE-/- mice. A strong correlation between Gls1 expression and plaque necrosis was also discovered in human atherosclerotic plaque. Most cells utilize glutamate dehydrogenase (Glud1) to fuel a-ketoglutarate (aKG) into the tricarboxylic acid (TCA) cycle for anapleurosis and epigenetic modifications. However, high- throughput transcriptional and metabolic profiling unexpectedly revealed that macrophage effector and clearance functions rely on a non-canonical transaminase pathway. Specifically, glutamate is channeled into the malate-aspartate shuttle by aspartate aminotransferase (GOT)-dependent transamination in order to meet the demand for high energy cytoskeletal rearrangements and cellular detoxification requirements. Macrophages are highly dependent on these series of reactions, as pharmacologic modulation of enzymes within these pathways impaired efferocytosis. Thus, our non-biased systems approach identifies that efficient clearance of ACs has a previously unknown reliance on non-canonical glutamine metabolism.
The full version of the manuscript can be find at:
https://pubmed.ncbi.nlm.nih.gov/34650273/(odnośnik otworzy się w nowym oknie)A new&views has been associated to this article (Glutamine gluttony of efferocytes:
https://www.nature.com/articles/s42255-021-00462-z(odnośnik otworzy się w nowym oknie))
We have developed a topological bioinformatic tool to integrate and map transcriptomic and metabolomic data on KEGG pathway (
https://biotest.hematometabolism.science/(odnośnik otworzy się w nowym oknie)).
A patent was filled from this project: Methods and pharmaceutical compositions for the treatment of cardiometabolic diseases # BIO19473
This work has been presented at Novartis in Cambridge, USA; EAS course in Vienna; Icola meeting in Seoul, Korea, Cardiovascular grand round in Maastritcht and the national society of atherosclerosis, NSFA, Biarritz, France.
A second major completion from this ERC grant involves: ‘GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls’. This manuscript by Murcy et al., is under review. Briefly, Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality and have been linked with both genetic and lifestyle-related risk factors. Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients, but the causal role and underlying mechanisms remain largely unknown. Here we asked how plasma glutamine-glutamate ratio (GGR) differed between people with and without CVD, and among CVD patients. Using the human MESA cohort, we found that the plasma GGR is an independent risk factor for carotid plaque progression. Using mouse models of atherosclerosis, we identified the underlying mechanism involving perturbation in hepatic metabolism, which rewires the pathophysiological dimension of the arterial wall of aortas during atherosclerotic plaque progression as determined by high-throughput transcriptional profiling and high-resolution structural biology imaging of aortas. A full version of this manuscript is included in this report.
This work has been presented at the SoMMM symposium in Bordeaux, EAS in Milan, Fusion meeting in Mexico, CardioSummit in Graz, EVBO and Gordon conference in Barcelona.
