AGC1/2, the mitochondrial aspartate-glutamate carriers

In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized within mitochondrial matrix to the cytosol in exchange for glutamate and a proton. A structure of an AGC carrier is not available yet but comparative 3D models were proposed. Moreover, transport assays performed by using the recombinant AGC1 and AGC2, reconstituted into liposome vesicles, allowed to explore the kinetics of those carriers and to reveal their specific transport properties. AGCs participate to a wide range of cellular functions, as the control of mitochondrial respiration, calcium signaling and antioxydant defenses. AGC1 might also play peculiar tissue-specific functions, as it was found to participate to cell-to-cell metabolic symbiosis in the retina. On the other hand, AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Accordingly, a mice model of AGC1 gene knock-out presented with growth delay and generalized tremor, with myelinisation defects. More recently, AGC was proposed to play a crucial role in tumor metabolism as observed from metabolomic studies showing that the asparate exported from the mitochondrion by AGC1 is employed in the regeneration of cytosolic glutathione. Therefore, given the central role of AGCs in cell metabolism and human pathology, drug screening are now being developed to identify pharmacological modulators of those carriers. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou

Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

Abstract Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients’ skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients’ skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes

Rapid Sonochemical Approach Produces Functionalized Fe3O4Nanoparticles with Excellent Magnetic, Colloidal, and Relaxivity Properties for MRI Application

Functionalized Fe3O4 nanoparticles (NPs) have emerged as a promising contrast agent for magnetic resonance imaging (MRI). Their synthesis and functionalization methodology strongly affect their performance in vivo. The methodology most used in the literature for the synthesis of Fe3O4 NPs is thermal decomposition, which has proven to be time-consuming, expensive, and laborious, as it requires further ligand exchange strategies to transfer the as-synthesized nanoparticles from organic to aqueous solvents. This work describes a rapid and facile sonochemical methodology to synthesize and functionalize Fe3O4 NPs with excellent physicochemical properties for MRI. This sonochemistry approach was used to produce, in 12 min, Fe3O4 NPs functionalized with polysodium acrylate (PAANa), trisodium citrate (CIT), branched polyethylenimine (BPEI), and sodium oleate. X-ray diffraction and transmission electron microscopy demonstrated that the NPs were composed of a single inverse spinel phase with an average diameter of 9–11 nm and a narrow size distribution. Mössbauer spectroscopy and magnetic measurements confirmed that the obtained NPs were transitioning to the superparamagnetic regime and possessed excellent magnetization saturation values (59–77 emu/g). Fourier transform infrared spectroscopy proved that the sonochemistry approach provided conditions that induced a strong interaction between Fe3O4 and the coating agents. Furthermore, dynamic light-scattering experiments evidenced that samples coated with PAANa, CIT, and BPEI possess colloidal stability in aqueous solvents. Emphasis must be placed on PAANa-coated NPs, which also presented remarkable colloidal stability under simulated physiological conditions. Finally, the obtained NPs exhibited great potential to be applied as an MRI contrast agent. The transverse relaxivity values of the NPs synthesized in this work (277–439 mM–1 s–1) were greater than those of commercial NPs and those prepared using other methodologies. Therefore, this work represents significant progress in the preparation of Fe3O4 NPs, providing a method to prepare high-quality materials in a rapid, cost-effective, and facile manner

Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: High (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas

Metabolic Plasticity of Tumor Cells: How They Do Adapt to Food Deprivation.

Dysregulated metabolism is a key hallmark of cancer cells and an enticing target for cancer treatment. Since the last 10 years, research on cancer metabolism has moved from pathway attention to network consideration. This metabolic complexity continuously adapt to new constraints in the tumor microenvironment. In this review, we will highlight striking changes in cancer cell metabolism compared to normal cells. Understanding this tumor metabolic plasticity suggests potential new targets and innovative combinatorial treatments for fighting cancer