| First Author | Azoulay IS | Year | 2022 |
| Journal | Redox Biol | Volume | 51 |
| Pages | 102253 | PubMed ID | 35247821 |
| Mgi Jnum | J:323331 | Mgi Id | MGI:6890029 |
| Doi | 10.1016/j.redox.2022.102253 | Citation | Azoulay IS, et al. (2022) ASIC1a senses lactate uptake to regulate metabolism in neurons. Redox Biol 51:102253 |
| abstractText | Lactate is a major metabolite largely produced by astrocytes that nourishes neurons. ASIC1a, a Na(+) and Ca(2+)-permeable channel with an extracellular proton sensing domain, is thought to be activated by lactate through chelation of divalent cations, including Ca(2+), Mg(2+) and Zn(2+), that block the channel pore. Here, by monitoring lactate-evoked H(+) and Ca(2+) transport in cultured mouse cortical and hippocampal neurons, we find that stereo-selective neuronal uptake of L-lactate results in rapid intracellular acidification that triggers H(+) extrusion to activate plasma membrane ASIC1a channels, leading to propagating Ca(2+) waves into the cytosol and mitochondria. We show that lactate activates ASIC1a at its physiological concentrations, far below that needed to chelate divalent cations. The L-isomer of lactate exerts a much greater effect on ASIC1a-mediated activity than the d-isomer and this stereo-selectivity arises from lactate transporters, which prefer the physiologically common L-lactate. The lactate uptake in turn results in intracellular acidification, which is then followed by a robust acid extrusion. The latter response sufficiently lowers the pH in the vicinity of the extracellular domain of ASIC1a to trigger its activation, resulting in cytosolic and mitochondrial Ca(2+) signals that accelerate mitochondrial respiration. Furthermore, blocking ASIC1a led to a robust mitochondrial ROS production induced by L-lactate. Together our results indicate that ASIC1a is a metabolic sensor, which by sensing extracellular pH drop triggered by neuronal lactate uptake with subsequent proton extrusion, transmits a Ca(2+) response that is propagated to mitochondria to enhance lactate catabolism and suppress ROS production. |
