Highlights d Lysine lactoylation occurs via a non-enzymatic acyl transfer from lactoylglutathione d Glycolytic enzymes are heavily modified by lactoylation d Glyoxalase 2 is the critical regulator for lactoylglutathione and lysine lactoylation d Glycolytic output is significantly repressed in glyoxalase 2 knockout cells

Specific immune responses are controlled by two counterbalancing mechanisms-co-stimulation and co-inhibition. Antigen receptors determine specificity, activate co-stimulation and/or co-inhibition, and interact with these co-stimulatory/co-inhibitory mechanisms to dictate the direction of the immune response, either positive or negative. Co-stimulatory or co-inhibitory ligands interact with their specific receptors and may indicate the context in which antigen is perceived by lymphocytes. Ligation of antigen receptors may activate only co-stimulatory or co-inhibitory mechanisms, and thus may influence secondarily the direction of the immune response. Furthermore, the activity of a given co-stimulator or co-inhibitory receptor is modified depending on signalling via the antigen receptor. If neither co-stimulators nor co-inhibitors are present, lymphocytes, activated in response to antigen receptor signalling, produce low levels of effector elements and then revert to inactivity. Co-inhibitors are defective in autoimmune disease.

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The pesticides paraquat (PQ) and maneb (MB) have been described as environmental risk factors for Parkinson's disease (PD), with mechanisms associated with mitochondrial dysfunction and reactive oxygen species generation. A combined exposure of PQ and MB in murine models and neuroblastoma cells has been utilized to further advance understanding of the PD phenotype. MB acts as a redox modulator through alkylation of protein thiols and has been previously characterized to inhibit complex III of the electron transport chain and uncouple the mitochondrial proton gradient. The purpose of this study was to analyze ATP-linked respiration and glycolysis in human neuroblastoma cells utilizing the Seahorse extracellular flux platform. Employing an acute, subtoxic exposure of MB, this investigation revealed a MB-mediated decrease in mitochondrial oxygen consumption at baseline and maximal respiration, with inhibition of ATP synthesis and coupling efficiency. Additionally, MB-treated cells showed an increase in nonmitochondrial respiration and proton leak. Further investigation into mitochondrial fuel flex revealed an elimination of fuel flexibility across all 3 major substrates, with a decrease in pyruvate capacity as well as glutamine dependency. Analyses of glycolytic function showed a substantial decrease in glycolytic acidification caused by lactic acid export. This inhibition of glycolytic parameters was also observed after titrating the MB dose as low as 6 μM, and appears to be dependent on the dithiocarbamate functional group, with manganese possibly potentiating the effect. Further studies into cellular ATP and NAD levels revealed a drastic decrease in cells treated with MB. In summary, MB significantly impacted both aerobic and anaerobic energy production; therefore, further characterization of MB's effect on cellular energetics may provide insight into the specificity of PD to dopaminergic neurons.