Journal
JOURNAL OF NEUROCHEMISTRY
Volume 153, Issue 2, Pages 203-215Publisher
WILEY
DOI: 10.1111/jnc.14971
Keywords
ASIC1a; cytosolic Ca2+ signaling; cytosolic Na+ signaling; mitochondrial Ca2+ signaling; mitochondrial Na+ signaling; NCLX
Categories
Funding
- Foundation for the National Institutes of Health [NS102452]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX05]
- Israel Science Foundation China [1210/14]
- National Natural Science Foundation of China [NS102452, 2018SHZDZX05, 81730095, 31461143004, 18JC1420302, 14, 1210]
- Science and Technology Commission of Shanghai Municipality [18JC1420302]
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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 Ca2+ sensitive and spatially specific fluorescent dyes, we investigated the role of ASIC1a in cytosolic Na+ and Ca2+ signals elicited by a mild extracellular drop from pH 7.4 to 7.0 and how these affect mitochondrial Na+ and Ca2+ signaling or metabolic activity. We show that in mouse primary cortical neurons, this small extracellular pH change triggers cytosolic Na+ and Ca2+ 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 Ca2+ 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.
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