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Abstract Background Nanoparticles are increasingly being used in medicine, cosmetics, food, and manufacturing. However, potential toxicity may limit the use of newly engineered nanoparticles. Prior studies have identified particle characteristics that are predictive of toxicity, although the mechanisms responsible for toxicity remain largely unknown. Nanoparticle treatment in cell culture, combined with high-throughput chemical screen allows for systematic perturbations of thousands of molecular targets against potential pathways of toxicity. The resulting data matrix, called chemical compendium, can provide insights into the mechanism of toxicity as well as help classify nanoparticles based on toxicity pathway. Results We performed unbiased screens of 1280 bioactive chemicals against a panel of four particles, searching for inhibitors of macrophage toxicity. Our hit compounds clustered upon inhibitors of kinases involved in phagocytosis, including focal adhesion kinase (FAK), with varying specificity depending on particles. Interestingly, known inhibitors of cell death including NLRP3 inflammasome inhibitor were unable to suppress particle-induced macrophage death for many of the particles. By searching for upstream receptors of kinases, we identified Cd11b as one of the receptors involved in recognizing a subset of particles. We subsequently used these hit compounds and antibodies to further characterize a larger panel of particles and identified hydrodynamic size as an important particle characteristic in Cd11b-mediated particle uptake and toxicity. Conclusions Our chemical compendium and workflow can be expanded across cell types and assays to characterize the toxicity mechanism of newly engineered nanoparticles. The data in their current form can also be analyzed to help design future high-throughput screening for nanoparticle toxicity. Graphical abstract

Mitochondrial supercomplex assembly may efficiently supply energy, yet its role remains controversial. Here, the authors show that SYK inhibitors increase supercomplex assembly and mitochondrial respiration in cells and can enhance exercise performance in mice.

DJ-1 is a multifunctional protein associated with pathomechanisms implicated in different chronic diseases including neurodegeneration, cancer and diabetes. Several of the physiological functions of DJ-1 are not yet fully understood; however, in the last years, there has been increasing evidence for a potential role of DJ-1 in the regulation of cellular metabolism. Here, we summarize the current knowledge on specific functions of DJ-1 relevant to cellular metabolism and their role in modulating metabolic pathways. Further, we illustrate pathophysiological implications of the metabolic effects of DJ-1 in the context of neurodegeneration in Parkinson´s disease.

The cellular content of mitochondria changes dynamically during development and in response to external stimuli, but the underlying mechanisms remain obscure. To systematically identify molecular probes and pathways that control mitochondrial abundance, we developed a high-throughput imaging assay that tracks both the per cell mitochondrial content and the cell size in confluent human umbilical vein endothelial cells. We screened 28,786 small molecules and observed that hundreds of small molecules are capable of increasing or decreasing the cellular content of mitochondria in a manner proportionate to cell size, revealing stereotyped control of these parameters. However, only a handful of compounds dissociate this relationship. We focus on one such compound, BRD6897, and demonstrate through secondary assays that it increases the cellular content of mitochondria as evidenced by fluorescence microscopy, mitochondrial protein content, and respiration, even after rigorous correction for cell size, cell volume, or total protein content. BRD6897 increases uncoupled respiration 1.6-fold in two different, non-dividing cell types. Based on electron microscopy, BRD6897 does not alter the percent of cytoplasmic area occupied by mitochondria, but instead, induces a striking increase in the electron density of existing mitochondria. The mechanism is independent of known transcriptional programs and is likely to be related to a blockade in the turnover of mitochondrial proteins. At present the molecular target of BRD6897 remains to be elucidated, but if identified, could reveal an important additional mechanism that governs mitochondrial biogenesis and turnover.