ASIC1a channels regulate mitochondrial ion signaling and energy homeostasis in neurons

Abstract

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.

Neurons Release Injured Mitochondria as “Help-Me” Signaling After Ischemic Stroke

“…In brief, neurons were washed twice with XF calibrant solution (#100840-000, Agilent, Palo Alto, CA, USA) and then placed in fresh assay medium. The basal, maximal, and ATP-coupled respiration was monitored after the addition of oligomycin (1 μM, #75351, Sigma-Aldrich, St. Louis, MO, USA), carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) (1 μM, #2920, Sigma-Aldrich, St. Louis, MO, USA) + sodium pyruvate (5 mM, #P2256, Sigma-Aldrich, St. Louis, MO, USA), antimycin A (4 μM, #A8674, Sigma-Aldrich, St. Louis, MO, USA), and rotenone (1 μM, #R8875, Sigma-Aldrich, St. Louis, MO, USA) as described previously ( Savic Azoulay et al, 2020 ). The assay was performed using Seahorse Bioscience XF96 extracellular flux analyzer (Agilent, Palo Alto, CA, USA), and the statistics were exported from Wave Desktop 2.4 software (Agilent, Palo Alto, CA, USA).…”

Targeting mitochondrial ion channels for cancer therapy

“…However, there is no clear evidence that targeting the mitochondrial channel is relevant for apoptosis induction, since no systematic studies have been carried out comparing the effect of membrane-impermeant and membrane-permeant inhibitors. In addition, recent evidence raises the possibility that even modulation of PM channels might affect mitochondrial ROS production and morphology [ 153 ] or mitochondrial membrane potential [ 154 ] by still unclarified mechanisms. In particular, Pardo and colleagues observed that lack or inhibition of the Kv10.1 channel of the PM by a membrane-impermeant specific antibody induced mitochondrial fragmentation and ROS production [ 153 ], while in the other work block of the ASIC1a acid-sensitive channel with membrane-impermeant Psalmotoxin-1 blocked mitochondrial Ca 2+ signals [ 154 ].…”

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

“…When comparing the topology of mitochondrial channels to that of plasma membrane-localized channels, there is a tendency to consider the matrix “intracellular” and IMS “extracellular.” Accessibility of IMM channels to membrane impermeant inhibitors such as toxins indicates that the extracellular domains of the channels face the IMS. Such is the case of, i.e., K V 1.3 [ 21 ], BK (K Ca 1.1) [ 22 ], and ASIC1a [ 23 ], whereas for other mitochondrial channels, the topology has not been established.…”

“…Accessibility of IMM channels to membrane impermeant inhibitors such as toxins indicates that the extracellular domains of the channels face the IMS. Such is the case of, i.e., K V 1.3 [21], BK (K Ca 1.1) [22], and ASIC1a [23], whereas for other mitochondrial channels, the topology has not been established.…”