LanCL1 attenuates ischemia-induced oxidative stress by Sirt3-mediated preservation of mitochondrial function

Xie, Zhen; Cao, Bingqing; Wang, Tao; Lei, Qi; Tai, Kang; Ge, Chao-Yuan; Gao, Wenjie; Hui, Hao

doi:10.1016/j.brainresbull.2018.07.017

Cited by 19 publications

(15 citation statements)

References 35 publications

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“…Regarding the signaling pathways downstream of LANCL1 and LANCL2, there are again several reports indicating shared features. Akt, AMPK, PGC-1α, and Sirtuins 1 and 3 lie downstream of LANCL2 and LANCL1 [ 8 , 9 , 11 , 34 ] and this report. Increased AMPK activity could, in theory, result from an increased ratio between pAMPK and total pAMPK or from an increased protein expression of AMPK with an unchanged ratio between the phosphorylated and the unphosphorylated protein.…”

Section: Discussionsupporting

confidence: 59%

“…Another observation pointing to a protective role of LANCL1 in neuronal cells comes from an in vitro study on a model of neuronal cell death caused by oxygen- and glucose-deprivation. The overexpression of LANCL1 reduced cell death through a signaling pathway dependent on Akt, PGC-1α, and Sirt3 activation [ 34 ]. Our observation that the overexpression of either LANCL1 or LANCL2 similarly increases cell respiration, sarcolipin, and UCP3 expression in rat L6 cells and that their combined silencing dramatically reduces mitochondrial DNA and the expression of sarcolipin and UCP3 ( Figure 5 ) are consistent with the general role of these proteins in stimulating cell glucose transport and mitochondrial respiration via an AMPK/PGC-1α-dependent mechanism ( Figure 4 , Figure 5 and [ 8 ]).…”

Section: Discussionmentioning

confidence: 99%

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LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Spinelli

Begani

Guida

et al. 2021

Molecular Metabolism

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Objective Abscisic acid (ABA) is a plant hormone also present and active in animals. In mammals, ABA regulates blood glucose levels by stimulating insulin-independent glucose uptake and metabolism in adipocytes and myocytes through its receptor LANCL2. The objective of this study was to investigate whether another member of the LANCL protein family, LANCL1, also behaves as an ABA receptor and, if so, which functional effects are mediated by LANCL1. Methods ABA binding to human recombinant LANCL1 was explored by equilibrium-binding experiments with [ 3 H]ABA, circular dichroism, and surface plasmon resonance. Rat L6 myoblasts overexpressing either LANCL1 or LANCL2, or silenced for the expression of both proteins, were used to investigate the basal and ABA-stimulated transport of a fluorescent glucose analog (NBDG) and the signaling pathway downstream of the LANCL proteins using Western blot and qPCR analysis. Finally, glucose tolerance and sensitivity to ABA were compared in LANCL2 −/− and wild-type (WT) siblings. Results Human recombinant LANCL1 binds ABA with a K d between 1 and 10 μM, depending on the assay (i.e., in a concentration range that lies between the low and high-affinity ABA binding sites of LANCL2). In L6 myoblasts, LANCL1 and LANCL2 similarly, i) stimulate both basal and ABA-triggered NBDG uptake (4-fold), ii) activate the transcription and protein expression of the glucose transporters GLUT4 and GLUT1 (4-6-fold) and the signaling proteins AMPK/PGC-1α/Sirt1 (2-fold), iii) stimulate mitochondrial respiration (5-fold) and the expression of the skeletal muscle (SM) uncoupling proteins sarcolipin (3-fold) and UCP3 (12-fold). LANCL2 −/− mice have a reduced glucose tolerance compared to WT. They spontaneously overexpress LANCL1 in the SM and respond to chronic ABA treatment (1 μg/kg body weight/day) with an improved glycemia response to glucose load and an increased SM transcription of GLUT4 and GLUT1 (20-fold) of the AMPK/PGC-1α/Sirt1 pathway and sarcolipin, UCP3, and NAMPT (4- to 6-fold). Conclusions LANCL1 behaves as an ABA receptor with a somewhat lower affinity for ABA than LANCL2 but with overlapping effector functions: stimulating glucose uptake and the expression of muscle glucose transporters and mitochondrial uncoupling and respiration via the AMPK/PGC-1α/Sirt1 pathway. Receptor redundancy may have been advantageous in animal evolution, given the role of the ABA/LANCL system in the insulin-independent stimulation of cell glucose uptake and energy metabolism.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Spinelli

Begani

Guida

et al. 2021

Molecular Metabolism

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“…During cerebral ischemia, nerve cells undergo irreversible damage due to the complete cessation of glucose and oxygen supply to the ischemic core [34][35][36][37]. Thus, ameliorating glucose metabolism and controlling neural cell apoptosis is of great importance to improve cerebral ischemia damage [38,39]. Modulation of miR-19a-3p expression impacted glycolytic enzymes and neuronal apoptosis, even though our results do not indicate the specific downstream effectors that are directly regulating these processes.…”

Section: Discussionmentioning

confidence: 63%

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Wang

Liu

et al. 2019

Cell Mol Biol Lett

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Background: Accumulating evidence has shown that altered microRNA (miR) modulation is implicated in the pathologies of ischemic stroke. However, it is unclear whether and how hsa-miR-19a-3p mediates cerebral ischemic injury. Herein, we investigated the functional role of miR-19a-3p in cerebral ischemic injury and explored its underlying regulatory mechanism. Methods: In vivo ischemic/reperfusion (I/R) neuronal injury and in vitro oxygenglucose deprivation (OGD) were established. Expression of miR-19a-3p was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Glucose uptake, lactate production, and apoptosis were determined. ADIPOR2 was predicted as a target of miR-19a-3p in silico and experimentally validated by qRT-PCR, Western blot analysis and luciferase assay assays. Results: MiR-19a expression was significantly downregulated and upregulated in rat neurons and astrocytes, respectively (P < 0.01). A significantly elevated level of miR-19a-3p was found in I/R and OGD models in comparison to sham/control groups (P < 0.01). Expression of the glycolysis enzyme markers LDHA, PKM2, HK2, Glut1 and PDK1, apoptosis-related factors levels, apoptosis, glucose uptake, and lactate production were significantly repressed by both I/R and OGD (P < 0.01 in each case). Moreover, miR-19a-3p mimic aggravated, while miR-19a-3p inhibitor alleviated, the above observations. Adipor2 was predicted and confirmed to be a direct target of miR-19a. Furthermore, restoration of Adipor2 reversed miR-19a-3p-induced effects. Conclusions: Collectively, our results indicate that elevated miR-19a-3p mediates cerebral ischemic injury by targeting ADIPOR2. MiR-19a-3p attenuation thus might offer hope of a novel therapeutic target for ischemic stroke injury treatment.

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“…Stroke is a leading cause of disability in adults, resulting in social and economic burdens worldwide [81,82]. Numerous attempts [1,2,13,[83][84][85][86][87][88][89][90][91][92][93][94] have been made to reveal the pathological mechanisms underlying cerebral ischemia and to design new drugs [2,[95][96][97][98][99] that reduce the effects of complications due to stroke [100][101][102]. Because all of the pharmacological interventions that have been tested to date have failed, new targets for novel therapies are needed.…”

Section: Discussionmentioning

confidence: 99%

Roles Played by the Na+/Ca2+ Exchanger and Hypothermia in the Prevention of Ischemia-Induced Carrier-Mediated Efflux of Catecholamines into the Extracellular Space: Implications for Stroke Therapy

et al. 2019

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The release of [ 3 H]dopamine ([ 3 H]DA) and [ 3 H]noradrenaline ([ 3 H]NA) in acutely perfused rat striatal and cortical slice preparations was measured at 37 °C and 17 °C under ischemic conditions. The ischemia was simulated by the removal of oxygen and glucose from the Krebs solution. At 37 °C, resting release rates in response to ischemia were increased; in contrast, at 17 °C, resting release rates were significantly reduced, or resting release was completely prevented. The removal of extracellular Ca 2+ further increased the release rates of [ 3 H]DA and [ 3 H]NA induced by ischemic conditions. This finding indicated that the Na + /Ca 2+ exchanger (NCX), working in reverse in the absence of extracellular Ca 2+ , fails to trigger the influx of Ca 2+ in exchange for Na + and fails to counteract ischemia by further increasing the intracellular Na + concentration ([Na + ] i ). KB-R7943, an inhibitor of NCX, significantly reduced the cytoplasmic resting release rate of catecholamines under ischemic conditions and under conditions where Ca 2+ was removed. Hypothermia inhibited the excessive release of [ 3 H] DA in response to ischemia, even in the absence of Ca 2+ . These findings further indicate that the NCX plays an important role in maintaining a high [Na + ] i , a condition that may lead to the reversal of monoamine transporter functions; this effect consequently leads to the excessive cytoplasmic tonic release of monoamines and the reversal of the NCX. Using HPLC combined with scintillation spectrometry, hypothermia, which enhances the stimulation-evoked release of DA, was found to inhibit the efflux of toxic DA metabolites, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL). In slices prepared from human cortical brain tissue removed during elective neurosurgery, the uptake and release values for [ 3 H]NA did not differ from those measured at 37 °C in slices that were previously maintained under hypoxic conditions at 8 °C for 20 h. This result indicates that hypothermia preserves the functions of the transport and release mechanisms, even under hypoxic conditions. Oxidative stress (H 2 O 2 ), a mediator of ischemic brain injury enhanced the striatal resting release of [ 3 H]DA and its toxic metabolites (DOPAL, quinone). The study supports our earlier findings that during ischemia transmitters are released from the cytoplasm. In addition, the major findings of this study that hypothermia of brain slice preparations prevents the extracellular calcium concentration ([Ca 2+ ] o )-independent non-vesicular transmitter release induced by ischemic insults, inhibiting Na + /Cl − -dependent membrane transport of monoamines and their toxic metabolites into the extracellular space, where they can exert toxic effects.

show abstract

LanCL1 attenuates ischemia-induced oxidative stress by Sirt3-mediated preservation of mitochondrial function

Cited by 19 publications

References 35 publications

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis

Roles Played by the Na+/Ca2+ Exchanger and Hypothermia in the Prevention of Ischemia-Induced Carrier-Mediated Efflux of Catecholamines into the Extracellular Space: Implications for Stroke Therapy

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