Mitochondrial dynamics in alveolar macrophages (AMs) are associated with sepsis-induced acute lung injury (ALI). In this study, we aimed to investigate whether changes in mitochondrial dynamics could alter the polarization of AMs in sepsis-induced ALI and to explore the regulatory mechanism of mitochondrial dynamics by focusing on sirtuin (SIRT)3-induced optic atrophy protein 1 (OPA1) deacetylation.
Results:
The AMs of sepsis-induced ALI showed imbalanced mitochondrial dynamics and polarization to the M1 macrophage phenotype. In sepsis, SIRT3 overexpression promotes mitochondrial dynamic equilibrium in AMs. However, 3-(1H-1, 2, 3-triazol-4-yl) pyridine (3TYP)-specific inhibition of SIRT3 increased the mitochondrial dynamic imbalance and pro-inflammatory polarization of AMs and further aggravated sepsis-induced ALI. OPA1 is directly bound to and deacetylated by SIRT3 in AMs. In AMs of sepsis-induced ALI, SIRT3 protein expression was decreased and OPA1 acetylation was increased. OPA1 acetylation at the lysine 792 amino acid residue (OPA1-K792) promotes self-cleavage and is associated with an imbalance in mitochondrial dynamics. However, decreased acetylation of OPA1-K792 reversed the pro-inflammatory polarization of AMs and protected the barrier function of alveolar epithelial cells in sepsis-induced ALI.
Innovation:
Our study revealed, for the first time, the regulation of mitochondrial dynamics and AM polarization by SIRT3-mediated deacetylation of OPA1 in sepsis-induced ALI, which may serve as an intervention target for precision therapy of the disease.
Conclusions:
Our data suggest that imbalanced mitochondrial dynamics promote pro-inflammatory polarization of AMs in sepsis-induced ALI and that deacetylation of OPA1 mediated by SIRT3 improves mitochondrial dynamic equilibrium, thereby ameliorating lung injury. Antioxid. Redox Signal. 41, 1014–1030.
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References
1.
AdaniyaSM, O-UchiJ, CypressMW, et al.Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology. Am J Physiol Cell Physiol, 2019; 316(5):C583–C604.
2.
AnandR, WaiT, BakerMJ, et al.The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol, 2014; 204(6):919–929; doi: 10.1083/jcb.201308006
3.
BakerN, PatelJ, KhachoM. Linking mitochondrial dynamics, cristae remodeling and supercomplex formation: How mitochondrial structure can regulate bioenergetics. Mitochondrion, 2019; 49:259–268; doi: 10.1016/j.mito.2019.06.003
4.
BalogluE, VelineniK, Ermis-KayaE, et al.Hypoxia aggravates inhibition of alveolar epithelial na-transport by lipopolysaccharide-stimulation of alveolar macrophages. Int J Mol Sci, 2022; 23(15):8315; doi: 10.3390/ijms23158315
5.
BenigniA, CassisP, ContiS, et al.Sirt3 Deficiency shortens life span and impairs cardiac mitochondrial function rescued by OPA1 gene transfer. Antioxid Redox Signal, 2019; 31(17):1255–1271; doi: 10.1089/ars.2018.7703
6.
BosLDJ, SciclunaBP, OngDSY, et al.Understanding heterogeneity in biologic phenotypes of acute respiratory distress syndrome by leukocyte expression profiles. Am J Respir Crit Care Med, 2019; 200(1):42–50; doi: 10.1164/rccm.201809-1808OC
7.
CenM, OuyangW, ZhangW, et al.MitoQ protects against hyperpermeability of endothelium barrier in acute lung injury via a Nrf2-dependent mechanism. Redox Bio, 2021; 41:101936; doi: 10.1016/j.redox.2021.101936
8.
ChengY, LuoD, ZhaoY, et al.N-Propargyl caffeate amide (PACA) prevents cardiac fibrosis in experimental myocardial infarction by promoting pro-resolving macrophage polarization. Aging (Albany NY), 2020; 12(6):5384–5398.
9.
ChimentiL, Morales-QuinterosL, PuigF, et al.Comparison of direct and indirect models of early induced acute lung injury. Intensive Care Med Exp, 2020; 8(Suppl 1):62; doi: 10.1186/s40635-020-00350-y
10.
CipolatS, Martins de BritoO, Dal ZilioB, et al.OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A, 2004; 101(45):15927–15932.
11.
CohenSB, GernBH, DelahayeJL, et al.Alveolar macrophages provide an early mycobacterium tuberculosis niche and initiate dissemination. Cell Host Microbe, 2018; 24(3):439–446.e4; doi: 10.1016/j.chom.2018.08.001
12.
Del DottoV, MishraP, VidoniS, et al.OPA1 isoforms in the hierarchical organization of mitochondrial functions. Cell Rep, 2017; 19(12):2557–2571.
13.
EisnerV, PicardM, HajnóczkyG. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol, 2018; 20(7):755–765; doi: 10.1038/s41556-018-0133-0
14.
FanEKY, FanJ. Regulation of alveolar macrophage death in acute lung inflammation. Respir Res, 2018; 19(1):50; doi: 10.1186/s12931-018-0756-5
15.
GuanYM, DiaoZL, HuangHD, et al.Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria. Amino Acids, 2021; 53(8):1229–1240; doi: 10.1007/s00726-021-03028-1
16.
GuoH, XieM, LiuW, et al.Inhibition of BTK improved APAP-induced liver injury via suppressing proinflammatory macrophages activation by restoring mitochondrion function. Int Immunopharmacol, 2022; 110:109036; doi: 10.1016/j.intimp.2022.109036
JiaCM, ZhangFW, WangSJ, et al.Tea polyphenols prevent sepsis-induced lung injury via promoting translocation of DJ-1 to mitochondria. Front Cell Dev Biol, 2021; 9:622507; doi: 10.3389/fcell.2021.622507
20.
JiangHL, YangHH, LiuYB, et al.L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during acute lung injury in mice. J Cell Physiol, 2022; 237(7):3030–3043; doi: 10.1002/jcp.30766
21.
KadomotoS, IzumiK, MizokamiA. Macrophage polarity and disease control. Int J Mol Sci, 2021; 23(1):144; doi: 10.3390/ijms23010144
22.
KurundkarD, KurundkarAR, BoneNB, et al.SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury. JCI Insight, 2019; 4(1):e120722; doi: 10.1172/jci.insight.120722
23.
LeeH, SmithSB, YoonY. The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure. J Biol Chem, 2017; 292(17):7115–7130; doi: 10.1074/jbc.M116.762567
24.
LiZ, ScottMJ, FanEK, et al.Tissue damage negatively regulates LPS-induced macrophage necroptosis. Cell Death Differ, 2016; 23(9):1428–1447; doi: 10.1038/cdd.2016.21
MishraP, CarelliV, ManfrediG, et al.Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab, 2014; 19(4):630–641; doi: 10.1016/j.cmet.2014.03.011
27.
MoserEK, FieldNS, OliverPM. Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia. Cell Mol Immunol, 2018; 15(5):480–492; doi: 10.1038/cmi.2016.69
28.
NayakDK, MendezO, BowenS, et al.Isolation and in vitro culture of murine and human alveolar macrophages. J Vis Exp, 2018; 134(134):57287; doi: 10.3791/57287
ParkI, KimM, ChoeK, et al.Neutrophils disturb pulmonary microcirculation in sepsis-induced acute lung injury. Eur Respir J, 2019; 53(3):1800786; doi: 10.1183/13993003.00786-2018
31.
RainboltTK, LebeauJ, PuchadesC, et al.Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteolytic activity during stress. Cell Rep, 2016; 14(9):2041–2049; doi: 10.1016/j.celrep.2016.02.011
32.
SamantSA, ZhangHJ, HongZ, et al.SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol, 2014; 34(5):807–819; doi: 10.1128/MCB.01483-13
33.
Sánchez-RodríguezR, TezzeC, AgnelliniAHR, et al.OPA1 drives macrophage metabolism and functional commitment via p65 signaling. Cell Death Differ, 2023; 30(3):742–752; doi: 10.1038/s41418-022-01076-y
34.
ShahD, DasP, AcharyaS, et al.Small Immunomodulatory molecules as potential therapeutics in experimental murine models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS). Int J Mol Sci, 2021; 22(5):2573; doi: 10.3390/ijms22052573
35.
SignorileA, SanteramoA, TammaG, et al.Mitochondrial cAMP prevents apoptosis modulating Sirt3 protein level and OPA1 processing in cardiac myoblast cells. Biochim Biophys Acta Mol Cell Res, 2017; 1864(2):355–366; doi: 10.1016/j.bbamcr.2016.11.022
36.
SingerM. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence, 2014; 5(1):66–72; doi: 10.4161/viru.26907
37.
SingerM, DeutschmanCS, SeymourCW, et al.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 2016; 315(8):801–810; doi: 10.1001/jama.2016.0287
38.
SunM, LiJ, MaoL, et al.p53 Deacetylation alleviates sepsis-induced acute kidney injury by promoting autophagy. Front Immunol, 2021; 12:685523; doi: 10.3389/fimmu.2021.685523
39.
SvedbergFR, BrownSL, KraussMZ, et al.The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation. Nat Immunol, 2019; 20(5):571–580; doi: 10.1038/s41590-019-0352-y
40.
TaoH, XuY, ZhangS. The Role of macrophages and alveolar epithelial cells in the development of ARDS. Inflammation, 2023; 46(1):47–55; doi: 10.1007/s10753-022-01726-w
WangQ, XuJ, LiX, et al.Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway. J Cell Physiol, 2019; 234(12):23495–23506; doi: 10.1002/jcp.28918
43.
WuJ, DengZ, SunM, et al.Polydatin protects against lipopolysaccharide-induced endothelial barrier disruption via SIRT3 activation. Lab Invest, 2020; 100(4):643–656; doi: 10.1038/s41374-019-0332-8
44.
YuJ, ShiJ, WangD, et al.Heme Oxygenase-1/Carbon Monoxide-regulated Mitochondrial dynamic equilibrium contributes to the attenuation of endotoxin-induced acute lung injury in rats and in lipopolysaccharide-activated macrophages. Anesthesiology, 2016; 125(6):1190–1201; doi: 10.1097/ALN.0000000000001333
ZengZ, YangY, DaiX, et al.Polydatin ameliorates injury to the small intestine induced by hemorrhagic shock via SIRT3 activation-mediated mitochondrial protection. Expert Opin Ther Targets, 2016; 20(6):645–652; doi: 10.1080/14728222.2016.1177023
47.
ZhangQ, WeiJ, LiuZ, et al.STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice. Redox Biol, 2022; 54:102367; doi: 10.1016/j.redox.2022.102367
48.
ZhangC, YangM, EricssonAC. Function of macrophages in disease: Current understanding on molecular mechanisms. Front Immunol, 2021; 12:620510; doi: 10.3389/fimmu.2021.620510
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