Acute lung injury (ALI) caused by endotoxin represents one of the common clinical emergencies. Mitochondria-associated endoplasmic reticulum membranes (MAM) serve as a critical link between mitochondria and endoplasmic reticulum (ER), which has an essential effect on maintaining intracellular homeostasis. As an important component of MAM, type-1 inositol-1,4,5-trisphosphate receptor (IP3R-1) mediates the ER-to-mitochondrial transport of Ca2+. This study explored the role of IP3R-1 and MAM in ALI. Besides the levels of inflammasome-associated components interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malonyldialdehyde (MDA) were increased in both bronchoalveolar lavage fluid (BALF) and serum, increased cross-sectional area of mitochondria, elevated MAM formation, and decreased respiratory control ratio (RCR) were observed within lung tissues collected in lipopolysaccharide (LPS)-treated mice, accompanied by upregulation of IP3R-1 in total lung lysates and MAM. Ca2+ uptake level in the mitochondria, production of reactive oxygen species (ROS) in the mitochondria, and the formation of MAM were elevated within LPS-treated MLE-12 cells, and all those changes in response to LPS were partly inhibited by knocking down of IP3R-1 expression in MLE-12 cells. Collectively, IP3R-1 has a critical effect on MAM formation and mitochondrial dysfunction, which could be innovative therapeutic targets for ALI caused by endotoxin.
SingerMDeutschmanCSSeymourCWShankar-HariMAnnaneDBauerMBellomoRBernardGRChicheJDCoopersmithCMHotchkissRSLevyMMMarshallJCMartinGSOpalSMRubenfeldGDvan der PollTVincentJLAngusDC, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3).JAMA2016;315:801–10
2.
CuthbertsonBHEldersAHallSTaylorJMacLennanGMackirdyFMackenzieSJ; Scottish Critical Care Trials Group; Scottish Intensive Care Society Audit Group. Mortality and quality of life in the five years after severe sepsis.Crit Care2013;17:R70
MillarFRSummersCGriffithsMJToshnerMRProudfootAG.The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities.Thorax2016;71:462–73
5.
ARDS Definition Task Force; RanieriVMRubenfeldGDThompsonBTFergusonNDCaldwellEFanECamporotaLSlutskyAS.Acute respiratory distress syndrome: the Berlin Definition.JAMA2012;307:2526–33
6.
ShiJYuJZhangYWuLDongSWuLWuLDuSZhangYMaD.PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury.Lab Invest2019;99:1795–809
7.
KimHJJeongJSKimSRParkSYChaeHJLeeYC.Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-kappaB/HIF-1alpha signaling pathway.Sci Rep2013;3:1142
8.
AlmannaiMEl-HattabAWAliMSoler-AlfonsoCScagliaF.Clinical trials in mitochondrial disorders, an update.Mol Genet Metab2020;131:1–13
9.
CsordásGRenkenCVárnaiPWalterLWeaverDButtleKFBallaTMannellaCAHajnóczkyG.Structural and functional features and significance of the physical linkage between ER and mitochondria.J Cell Biol2006;174:915–21
10.
MurleyALacknerLLOsmanCWestMVoeltzGKWalterPNunnariJ.ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast.Elife2013;2:e422
11.
RizzutoRDe StefaniDRaffaelloAMammucariC.Mitochondria as sensors and regulators of calcium signalling.Nat Rev Mol Cell Biol2012;13:566–78
12.
PatergnaniSDaneseABouhamidaEAguiariGPreviatiMPintonPGiorgiC.Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer.Int J Mol Sci2020;21:8323
13.
SzabadkaiGBianchiKVárnaiPDe StefaniDWieckowskiMRCavagnaDNagyAIBallaTRizzutoR.Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels.J Cell Biol2006;175:901–11
14.
RizzutoRBriniMMurgiaMPozzanT.Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria.Science1993;262:744–7
15.
KirichokYKrapivinskyGClaphamDE.The mitochondrial calcium uniporter is a highly selective ion channel.Nature2004;427:360–4
16.
ArrudaAPPersBMParlakgülGGüneyEInouyeKHotamisligilGS.Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity.Nat Med2014;20:1427–35
17.
RowlandAAVoeltzGK.Endoplasmic reticulum-mitochondria contacts: function of the junction.Nat Rev Mol Cell Biol2012;13:607–25
18.
Area-GomezEDel Carmen Lara CastilloMTambiniMDGuardia-LaguartaCde GroofAJMadraMIkenouchiJUmedaMBirdTDSturleySLSchonEA.Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.Embo J2012;31:4106–23
19.
TubbsETheureyPVialGBendridiNBravardAChauvinMAJi-CaoJZoulimFBartoschBOvizeMVidalHRieussetJ.Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance.Diabetes2014;63:3279–94
20.
WieckowskiMRGiorgiCLebiedzinskaMDuszynskiJPintonP.Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells.Nat Protoc2009;4:1582–90
21.
Matute-BelloGDowneyGMooreBBGroshongSDMatthayMASlutskyASKueblerWM; Acute Lung Injury in Animals Study Group. An official American thoracic society workshop report: features and measurements of experimental acute lung injury in animals.Am J Respir Cell Mol Biol2011;44:725–38
22.
DongSAZhangYYuJBLiXYGongLRShiJKangYY.Carbon monoxide attenuates lipopolysaccharide-induced lung injury by mitofusin proteins via p38 MAPK pathway.J Surg Res2018;228:201–10
23.
BernhardWHaguenauFGautierAOberlingC.[Submicroscopical structure of cytoplasmic basophils in the liver, pancreas and salivary gland; study of ultrafine slices by electron microscope].Z Zellforsch Mikrosk Anat1952;37:281–300
24.
VanceJE.Phospholipid synthesis and transport in mammalian cells.Traffic2105;16:1–18
25.
DuchenMR.Ca(2+)-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons.Biochem J1992;283:41–50
26.
HaileyDWRamboldASSatpute-KrishnanPMitraKSougratRKimPKLippincott-SchwartzJ.Mitochondria supply membranes for autophagosome biogenesis during starvation.Cell2010;141:656–67
27.
GalmesRHoucineAvan VlietARAgostinisPJacksonCLGiordanoF.ORP5/ORP8 localize to endoplasmic reticulum-mitochondria contacts and are involved in mitochondrial function.EMBO Rep2016;17:800–10
28.
MochidaKOikawaYKimuraYKirisakoHHiranoHOhsumiYNakatogawaH.Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus.Nature2015;522:359–62
29.
BononiABonoraMMarchiSMissiroliSPolettiFGiorgiCPandolfiPPPintonP.Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner.Cell Death Differ2013;20:1631–43
30.
HornerSMLiuHMParkHSBrileyJGaleMJ.Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.Proc Natl Acad Sci U S A2011;108:14590–5
31.
PaillussonSStoicaRGomez-SuagaPLauDHWMuellerSMillerTMillerCCJ. There’s something wrong with my MAM; the ER-mitochondria axis and neurodegenerative diseases.Trends Neurosci2016;39:146–57
32.
SesslerCNBloomfieldGLFowlerAA3rd. Current concepts of sepsis and acute lung injury.Clin Chest Med1996;17:213–35
33.
HowellMDDavisAM.Management of sepsis and septic shock.JAMA2017;317:847–8
34.
FriedmanJRLacknerLLWestMDiBenedettoJRNunnariJVoeltzGK.ER tubules mark sites of mitochondrial division.Science2011;334:358–62
35.
CárdenasCMillerRASmithIBuiTMolgóJMüllerMVaisHCheungKHYangJParkerIThompsonCBBirnbaumMJHallowsKRFoskettJK.Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria.Cell2010;142:270–83
36.
ThomasGAslanJEThomasLShindePShindeUSimmenT.Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease.J Cell Sci2017;130:1865–76
37.
VannuvelKRenardPRaesMArnouldT.Functional and morphological impact of ER stress on mitochondria.J Cell Physiol2013;228:1802–18
38.
HayashiTSuTP.Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.Cell2007;131:596–610
39.
XuHGuanNRenYLWeiQJTaoYHYangGSLiuXYBuDFZhangYZhuSN.IP3R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model.BMC Nephrol2018;19:140
40.
SzabadkaiGDuchenMR.Mitochondria: the hub of cellular Ca2+ signaling.Physiology2008;23:84–94
41.
DesouzaNReikenSOndriasKYangYMatkovichSMarksAR.Protein kinase A and two phosphatases are components of the inositol 1,4,5-trisphosphate receptor macromolecular signaling complex.J Biol Chem2002;277:39397–400
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
