ASIC1a channels regulate mitochondrial ion signaling and energy homeostasis in neurons.

Acid-sensing ion channel 1a (ASIC1a) is well-known to play a major pathophysiological role during brain ischemia linked to acute acidosis of ~pH 6, whereas its function during physiological brain activity, linked to much milder pH changes, is still poorly understood. Here, by performing live cell imaging utilizing Na ⁺ and Ca ²⁺ sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na ⁺ and Ca ²⁺ signals elicited by a mild extracellular drop from pH 7.4 to 7.0 and how these affect mitochondrial Na ⁺ and Ca ²⁺ signaling or metabolic activity. We show that in mouse primary cortical neurons, this small extracellular pH change triggers cytosolic Na ⁺ and Ca ²⁺ waves that propagate to mitochondria. Inhibiting ASIC1a with Psalmotoxin 1 or ASIC1a gene knockout blocked not only the cytosolic but also the mitochondrial Na ⁺ and Ca ²⁺ signals. Moreover, physiological activation of ASIC1a by this pH shift enhances mitochondrial respiration and evokes mitochondrial Na ⁺ signaling even in digitonin-permeabilized neurons. Altogether our results indicate that ASIC1a is critical in linking physiological extracellular pH stimuli to mitochondrial ion signaling and metabolic activity and thus is an important metabolic sensor.
(© 2020 International Society for Neurochemistry.)