ASIC1a senses lactate uptake to regulate metabolism in neurons

Azoulay, Ivana Savic; Qi, Xin; Rozenfeld, Maya; Liu, Fan; Hu, Qin; Nissim, Tsipi Ben Kasus; Stavsky, Alexandra; Zhu, Michael X.; Xu, Tian‐Le; Sekler, Israel

doi:10.1016/j.redox.2022.102253

Cited by 17 publications

(12 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It mediates cardiac ischemia–reperfusion injury (IRI), and polymorphisms in its genetic locus are associated with ischemic disease, the therapeutic blockade of ASIC1a reduces cell death, fibrosis, and adverse remodeling, and improves cardiac function [ 43 ]. Studies indicate that ASIC1a, which senses the extracellular pH drop triggered by neuronal physiological L-lactate uptake, transmits a Ca 2+ response that is propagated to mitochondria to enhance lactate catabolism and mitochondrial respiration [ 44 , 45 ]. We previously demonstrated that ASIC1a expression was higher in AA rat articular cartilage than in that of normal rats.…”

Section: Discussionmentioning

confidence: 99%

Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis

Zai

Qian

et al. 2022

J Transl Med

View full text Add to dashboard Cite

Background Destruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis (RA). Acid-sensing ion channel 1a (ASIC1a) is a key molecule that mediates the destruction of RA articular cartilage. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear. Methods We treated rat articular chondrocytes with an acidic environment, analyzed the expression levels of mitochondrial stress protein HSP10, ClpP, LONP1 by q-PCR and immunofluorescence staining. Transmission electron microscopy was used to analyze the mitochondrial morphological changes. Laser confocal microscopy was used to analyze the Ca2+, mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) level. Moreover, ASIC1a specific inhibitor Psalmotoxin 1 (Pctx-1) and Ethylene Glycol Tetraacetic Acid (EGTA) were used to observe whether acid stimulation damage mitochondrial function through Ca2+ influx mediated by ASIC1a and whether pretreatment with estrogen could counteract these phenomena. Furthermore, the ovariectomized (OVX) adjuvant arthritis (AA) rat model was treated with estrogen to explore the effect of estrogen on disease progression. Results Our results indicated that HSP10, ClpP, LONP1 protein and mRNA expression and mitochondrial ROS level were elevated in acid-stimulated chondrocytes. Moreover, acid stimulation decreased mitochondrial membrane potential and damaged mitochondrial structure of chondrocytes. Furthermore, ASIC1a specific inhibitor PcTx-1 and EGTA inhibited acid-induced mitochondrial abnormalities. In addition, estrogen could protect acid-stimulated induced mitochondrial stress by regulating the activity of ASIC1a in rat chondrocytes and protects cartilage damage in OVX AA rat. Conclusions Extracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the damage of rat articular chondrocytes. Estrogen antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. Our study provides new insights into the protective effect and mechanism of action of estrogen in RA.

show abstract

Section: Discussionmentioning

confidence: 99%

Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis

Zai

Qian

et al. 2022

J Transl Med

View full text Add to dashboard Cite

show abstract

“…The therapeutic blockade of ASIC1a reduces cell death, fibrosis, and adverse remodeling, and improves cardiac function [36]. Studies indicate that ASIC1a, which senses the extracellular pH drop triggered by neuronal physiological L-lactate uptake, transmits a Ca 2+ response that is propagated to mitochondria to enhance lactate catabolism and mitochondrial respiration [37,38]. We previously demonstrated that ASIC1a expression was higher in AA rat articular cartilage than in that of normal rats.…”

Section: Discussionmentioning

confidence: 99%

Estrogen antagonizes ASIC1a-induced chondrocyte Mitochondrial stress in Rheumatoid Arthritis

Zai

Qian

et al. 2022

Preprint

View full text Add to dashboard Cite

Destruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear. Here, we found that acid-sensing ion channel 1a (ASIC1a) mediates intracellular Ca2+ overload in response to extracellular acidification, which leads to mitochondrial stress in rat chondrocytes. Estrogen antagonizes Ca2+ overload-induced mitochondrial stress by inhibiting the activity of ASIC1a, thereby protecting articular chondrocytes in vivo and in vitro . These findings suggest that extracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the death of rat articular chondrocytes. Estrogen is a beneficial factor that antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. In summary, our study provides new insights into the protective effect and mechanism of action of estrogen in rheumatoid arthritis.

show abstract

“…The impairments of gamma and theta-gamma oscillations induced by lactate might result from diverse effects such as (1) attenuation of intrinsic neuronal excitability, (2) reduced neurotransmitter release, and (3) altered activation of postsynaptic glutamatergic and GABAergic receptors. These effects might be mediated by ( 4) local shortage of ATP by drop out of glycolysis and limitations in transport, conversion and oxidation of lactate (Dienel, 2019;Lucas et al, 2018;Lujan et al, 2016), ( 5) increased production of NO by the Ca 2+ -sensitive neuronal NO synthase partially inhibiting mitochondrial respiration (Azoulay et al, 2022;Brown, 2010;Hardingham et al, 2013;Kovács et al, 2009), (6) intracellular acidification by ATP hydrolysis and the H + -coupled neuronal MCT2 (Azoulay et al, 2022;Halestrap, 2013;Pesi et al, 2020;Xiang & Bergold, 2000), (7) shift in the cytosolic NAD + /NADH ratio (Bak & Schousboe, 2017;Hung et al, 2011;Ivanov et al, 2011), ( 8) activation of the HCAR1 by lactate (Bozzo et al, 2013;Briquet et al, 2022;Gilbert et al, 2006), and/ or (9) activation of purinergic (P2X) and adenosine (A1) receptors by extracellular ATP and adenosine (Cunha, 2016;Illes et al, 2019;Schulz et al, 2012;Serrano et al, 2006). The precise subcellular mechanisms underlying impairments of gamma oscillations are widely unknown, however, and require further morphological, biochemical, electrophysiological and imaging studies.…”

Section: Gamma and Theta-gamma Oscillationsmentioning

confidence: 99%

“…Lactate has been reported to substantially support neuronal survival, synthesis of ATP and neurotransmitters, neural activity control and synaptic plasticity in dissociated primary neuronal cultures (in vitro) and the intact cortex (in vivo) (Azoulay et al, 2022; Bouzier‐Sore et al, 2003; Bozzo et al, 2013; Mächler et al, 2016; Schousboe et al, 1997; Sobieski et al, 2017; Suzuki et al, 2011; Wyss et al, 2011). These studies provided valuable insights into the potentials of lactate in neuronal energy metabolism and signaling.…”

Section: Introductionmentioning

confidence: 99%

Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations

Kann

2023

Journal of Neurochemistry

View full text Add to dashboard Cite

Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30–70 Hz) and theta‐gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation–inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus‐induced neural population responses and intermittent sharp wave‐ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave‐ripples reflecting enhanced adenosine‐5′‐triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast‐spiking, γ‐aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation.image

show abstract

ASIC1a senses lactate uptake to regulate metabolism in neurons

Cited by 17 publications

References 44 publications

Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis

Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis

Estrogen antagonizes ASIC1a-induced chondrocyte Mitochondrial stress in Rheumatoid Arthritis

Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations

Contact Info

Product

Resources

About