September 27, 2018
Division of Biology Seminar Series to host Rodrigo Franco Cruz Sept. 28
The Division of Biology will host Rodrigo Franco Cruz, University of Nebraska, Lincoln, on 4 p.m. Sept. 28 in 221 Ackert Hall as part of its seminar series.
Cruz will present "Mitochondrial metabolism and autophagic signaling in glial cell survival against xenobiotic-induced apoptosis."
Cruz will talk of how astrocytes play an essential role in brain functions by regulating neuronal excitability and homeostasis, and they are the first line of defense against xenobiotics crossing into the brain. Glutathione, or GSH, catalyzes the detoxification of reactive oxygen species, or ROS, toxic metabolic electrophiles and xenobiotics. Autophagy is a homeostatic response that is involved in cellular adaptation to stress conditions. In this work, they demonstrate for the first time that: 1) astrocytes adapt their mitochondrial metabolism to fuel the detoxification of electrophiles via the GSH system; and 2) that autophagy contributes to apoptotic cell death induced by xenobiotics. Inorganic arsenic — iAs: As2O3 and NaAsO2 — induced an increase in de novo GSH synthesis in primary rat cortical astrocytes, which was paralleled by an enhanced mitochondrial respiratory reserve capacity. iAs accumulation and toxicity was potentiated by inhibition of de novo GSH synthesis, and by blockage of the transport of GSH-arsenic adducts — AsIIIGS3 — via the multidrug resistance associated protein 1, MRP1/ABCC1. Metabolomic — 13C — flux analysis revealed that arsenic induced a switch of carbon metabolism from glycolysis to the anaplerotic generation of glutamate via the tricarboxylic acid — TCA — cycle. Inhibition of free fatty acid — FFA — oxidation, or FAO, the mitochondrial pyruvate carrier — MPC1 — or the mitochondrial electron transport chain, or ETC, had no effect on astrocytes’ survival but it increased iAs accumulation and toxicity. iAs toxicity was mediated by apoptosis and was paralleled by an increase in autophagy flux. However, inhibition of autophagy and the AMP-activated protein kinase, or AMPK, protected astrocytes against iAs. On the other hand, osmotic activation of the stress-activated protein kinase p38 promoted astrocytes’ survival upon iAs exposure. The results reveal that the metabolic plasticity of the mitochondria in astrocytes fuels the GSH/ MRP1 system for the detoxification of neurotoxic electrophiles such as iAs. Furthermore, these findings highlight the central role of glial carbon metabolism in brain redox homeostasis and defense. Finally, to our surprise, iAs-induced autophagy promotes apoptosis while activation of the SAPK p38 protected against it.
If you would like to visit with Cruz, please contact Jeroen Roelofs at firstname.lastname@example.org.