Iron Supplementation Delays Aging and Extends Cellular Lifespan Los Ntawm Kev Muaj Peev Xwm Ntawm Mitochondrial Function Ⅱ
Mar 23, 2023
3.2. Iron Supplementation Ua kom Oxidative Stress Resistance
Cellular aging yog txuam nrognce oxidative kev nyuaj siabuas ua rau cov kab mob lom thiab txo cov kab mob muaj hnub nyoog [34]. Txij li cov hlau supplementation ncua kev laus, peb tshawb xyuas nws cov nyhuvoxidative kev nyuaj siab. Peb siv iboxidative kev nyuaj siabinducer compound, hydrogen peroxide (H2O2), txhawm rau kuaj oxidative tsis kam ntawm cov hlwb. Cells yog thawj zaug loj hlob nyob rau hauv lub xub ntiag ntawm hlau mus rau theem nyob ruaj ruaj (72 h) nyob rau hauv SD nruab nrab. Tom qab ntawd, cov hlwb raug ntxuav thiab incubated nrog ntau qhov sib txawv ntawm H2O2 hauv YPD nruab nrab thiab loj hlob rau 24 teev.OxidativeKev ntxhov siab tiv thaiv tau txheeb xyuas los ntawm kev sib piv cov cell loj hlob ntawm H2O2- kho cov hlwb nrog kev tswj tsis tau kho. Peb pom tias cov hlwb ntxiv nrog cov hlau tiv taus oxidative kev nyuaj siab piv rau kev tswj hwm (Figures2a thiab S3). Txhawm rau paub meej tias cov hlau ntxiv muab kev tiv thaiv rau oxidative kev nyuaj siab, BPS tau ntxiv rau hlau thiab cell loj hlob nrog H2O2 raug tshuaj xyuas. Qhov sib ntxiv ntawm BPS txo cov oxidative kev nyuaj siab ntawm cov hlau ntxiv (Daim duab2b). Cov txiaj ntsig no cuam tshuam nrog lub luag haujlwm ntawm cov hlau ntxiv hauv kev ncua kev laus thiab ncua lub cellular lifespan.
3.3. Iron Supplementation Potentiates Mitochondrial Functions
Mitochondria yog lub cellular hub loj rau kev siv hlau thiab cov metabolism [35–38]. Kev poob qis hauv kev ua haujlwm mitochondrial yog txuam nrog kev laus [39–43]. Hlau ua hauj lwm raws li ib tug cofactor ntawm ob peb mitochondrial proteins, xws li hlau-sulfur pawg thiab heme-muaj proteins [44-46]. Cov proteins uas muaj hlau no koom nrog hauv lub voj voog mitochondrial tricarboxylic acid (TCA) thiab electron thauj saw (ETC) (Daim duab 3a). Peb tau tshawb xyuas seb qhov nce hauv cellular lifespan los ntawm cov hlau supplementation yuav tsum tau ua mitochondrial zog. Txhawm rau kuaj qhov no, peb tau txheeb xyuas qhov kev qhia ntawm mitochondrial TCA lub voj voog cov noob. Peb pom tias kev ntxiv cov hlau tseem ceeb ua rau muaj kev nthuav qhia ntawm ntau lub voj voog TCA (Figures 3b thiab S4a). TCA-cycle metabolites -ketoglutarate thiab oxaloacetate tuaj yeem tsim glutamate thiab aspartate los ntawm cataplerotic cov tshuaj tiv thaiv hauv mitochondria (Daim duab 3a). Cov amino acids no yog siv rau hauv biosynthesis ntawm cov protein, lipids, thiab nucleotides [47-49]. Interestingly, kev qhia ntawm glutamate (GDH1 thiab GDH3) thiab aspartate (AAT1 thiab AAT2) biosynthetic noob tau txo qis hauv cov hlau ntxiv (Daim duab 3c). Qhov kev qhia no qhia tau hais tias kev txhawb nqa hlau txhawb kev khaws cia es tsis txhob siv TCA lub voj voog nruab nrab. Raws li kev pom zoo nrog lub tswv yim no, gene qhia ntawm mitochondrial anaplerotic pathway noob (PYC1, PYC2, thiab GDH2) tau nce ntxiv hauv cov hlwb uas muaj hlau ntxiv (Daim duab 3c). PYC1 thiab PYC2 encode pyruvate carboxylase uas converts pyruvate rau oxaloacetate. GDH2 encodes glutamate dehydrogenase uas synthesizes -ketoglutarate los ntawm glutamate. Ua ke, cov txiaj ntsig no qhia tias kev ntxiv cov hlau teeb tsa cov hlwb hauv lub xeev metabolic uas nyiam cov neeg mob anaplerosis thiab tiv thaiv kab mob cataplerosis los txhawb TCA lub voj voog metabolites.
Daim duab 3.Iron supplementation txhim khu kev ua haujlwm mitochondrial. (a) Lub ntsiab lus ntawm mitochondrialTCA (tricarboxylic acid) voj voog thiab ETC (electron thauj saw) nrog cov cataplerotic loj thiabCov tshuaj tiv thaiv analerotic yog qhia. (b) Cov kab mob prototrophic poov xab tau incubated nrog 100µM FeSO4 thiab loj hlob hauv SD nruab nrab rau 8 h ntawm 30◦C. RNA tau muab rho tawm los ntawm cov kab lis kev cai thiab covKev nthuav qhia ntawm TCA lub voj voog cov noob tau txheeb xyuas los ntawm ntau yam RT-PCR. (c) Kev nthuav qhiatsom xam ntawm cov noob cataplerotic (GDH1, GDH 3, AAT1,thiabAAT2) thiab anaplerotic genes (PYC 1, PYC 2,thiabGDH 2) tau ua los ntawm ntau yam RT-PCR. (d) Kev tsom xam ntawm ETC cov noob tau ua los ntawmTus nqi RT-PCR. Statistical tseem ceeb (*p < 0.05) was determined by Student's t- kuaj.
TCA lub voj voog cov tshuaj tiv thaiv tsim NADH thiab FADH2 uas yog oxidized los ntawm ETC complexes I thiab II thiab yuav tsum tau rau lub functionality ntawm TCA voj voog (Daim duab3a). Txawm tiasS. cerevisiaetsis muaj complex I, txo qhov sib npaug yog pauv mus rau cov kab mob ua pa los ntawm NADH dehydrogenases. Succinate dehydrogenase ua lub luag haujlwm tseem ceeb thiab koom nrog hauv TCA lub voj voog thiab ETC complex II (Daim duab3a). Strikingly, kev qhia ntawm succinate dehydrogenase (SDH1thiabSDH 2) tau raug kho siab heev ntawm tag nrho cov tshuaj ntsuam TCA lub voj voog noob (Daim duab3b, d). Cov txiaj ntsig no qhia tau tias TCA lub voj voog flux txuas ntxiv mus rau ETC es tsis txhob sib sau ua ke ib qho nruab nrab. Ib yam li ntawd, qhov kev qhia ntawm tag nrho lwm cov noob ntawm ETC complexes tau nce siab hauv cov hlwb ntxiv (Daim duab3d). ETC yog txuam nrog cov tiam ntawm reactive oxygen hom (ROS), uas tswj cov kev qhia ntawm lubSOD 2noob [50]. Nws encodes ib manganese-superoxide dismutase (MnSOD) uas yog tus thawj scavenger ntawm mitochondrial superoxide.SOD 2gene qhia tau upregulated nyob rau hauv cov hlau-ntxiv hlwb (Ntxiv daim duab S4a) uas yog raws li cov kev qhia ntawm ETC genes. Peb tau soj ntsuam ntxiv txog qhov mitochondrial membrane muaj peev xwm (MMP) uas yog tsim los ntawm cov twj tso kua mis proton ntawm ETC complexes I, III, thiab IV. Peb pom tias cov hlau supplementation tau nce MMP ntawm cov hlwb (Cov Duab Ntxiv S4b). Tom qab ntawd peb soj ntsuam cov qauv ntawm mitochondria siv fluorescence microscopy. Peb pom tias cov hlau supplementation tiv thaiv cov fragmentation ntawm mitochondria (Supplementary Figure S4c). Ua ke, cov txiaj ntsig no qhia tau hais tias cov hlau ntxiv potentiates lub mitochondrial zog ntawm cov hlwb.
3.4. Iron Supplementation nce qib ATP uas yuav tsum tau muaj rau kev txuas ntxiv ntawm Cellular Lifespan
Mitochondrial TCA lub voj voog cov tshuaj tiv thaiv ua rau txo qhov sib npaug NADH thiab FADH2 uas hloov hluav taws xob rau ETC thiab tsim cov adenosine triphosphate (ATP) los ntawm oxidative phosphorylation (OXPHOS) (Daim duab3a). Txij li thaum qhia txog TCA lub voj voog thiab ETC cov noob tau txhim kho los ntawm kev ntxiv hlau, peb tau sim nws cov nyhuv ntawm ATP synthesis. Raws li kev pom zoo nrog kev qhia profile ntawm mitochondrial TCA lub voj voog, ETC gene qhia thiab ATP qib siab hauv cov hlwb ntxiv (Daim duab4a). Tom qab ntawd peb nug seb ATP puas xav tau rau kev txuas ntxiv ntawm lub neej ntawm cov hlau txuas ntxiv. Peb inhibited ATP synthesis thiab ntsuas CLS ntawm poov xab. Antimycin A (AMA) yog ib qho inhibitor ntawm ATP synthesis uas khi rau complex III thiab blocks electron hloov hauv mitochondrial ETC [51]. Peb thawj zaug tshuaj xyuas qib ATP thiab pom tias kev kho AMA inhibits ATP synthesis (Daim duab4b). Peb tau sim ntxiv qhov cuam tshuam ntawm AMA ntawm cov cellular lifespan ntawm cov hlau ntxiv. Cov poov xab tau incubated nrog hlau thiab AMA hauv SD nruab nrab. Kev loj hlob ntawm cov hlwb mus txog saturation tom qab 24 teev (Ntxiv daim duab S5). Tom qab ntawd, peb ntsuas qhov ciaj sia taus thiab pom tias AMA kev kho mob inhibits cov hlau supplementation-mediated extension ntawm lifespan (Daim duab4c). Ua ke, cov kev tshawb pom no qhia tau hais tias cov hlau supplementation nce qib ATP uas yuav tsum tau rau kev ncua ntawm cellular lifespan. Peb kuj tau pom tias lub neej ntawm AMA-kho hlwb tau qis dua li kev tswj hwm (Daim duab4c), ntxiv kev lees paub tias qhov tsis muaj peev xwm los ua ke ATP cuam tshuam txog lub neej.
3.5. Iron Supplementation inhibits Accelerated Aging of AMPK Knockout Mutant
AMPK yog tus thawj tswj hwm ntawm cellular zog homeostasis [20,21]. Cov tib neeg tau txais txiaj ntsig zoo ntawm AMPK hauv cov poov xabS. cerevisiaeyog Snf1 protein [52]. AMPK qhib cov haujlwm mitochondrial los tsim ATP raws li lub zog txwv. Cov ntawv ceeb toom tsis ntev los no tau qhia tias kev poob qis hauv mitochondrial kev ua haujlwm nrog lub hnub nyoog tshwm sim hauv ib feem los ntawm kev ua haujlwm tsis zoo ntawm AMPK hauv cov kab mob muaj hnub nyoog sib txawv [53,54]. Yog li, qhov tsis muaj AMPK kev ua haujlwm cuam tshuam rau kev ua haujlwm mitochondrial thiab cuam tshuam ntau lub zog ntawm tes nrog rau cov metabolism, tiv thaiv kev ntxhov siab, thiab kev ciaj sia ntawm tes uas yog qhov tseem ceeb tshaj plaws ntawm kev laus thiab kev ua neej. Raws li kev tshawb fawb yav dhau los, pebpom tias covsnf1 uaknockout kev hloov pauv cuam tshuam rau qib ATP, tiv thaiv oxidative kev nyuaj siab, thiab lifespan (Daim duab5a–c).
Daim duab 5.Iron supplementation cawm qhov kev laus ntawm AMPK knockout mutant. Covpoov xab prototrophic qus-hom thiab AMPK knockout mutant (snf1 ua∆) cov kab mob tau loj hlob mus nyob ruaj khovtheem hauv SD nruab nrab rau 72 h ntawm 30◦C. (a) ATP tsom xam ntawm cov tsiaj qus thiabsnf1 ua∆ hom kab mob. (b) Oxidativekev ntxhov siab ntawm cov tsiaj qus thiabsnf1 ua∆ hom kab mob sib txawv H2O2 concentrations. (c) Chronologicallifespan (CLS) tsom xam ntawm cov tsiaj qus thiabsnf1 ua∆ hom kab mob. (d) ATP tsom xam ntawm cov tsiaj qus thiabsnf1 ua∆ hom kab mobincubated nrog ntau qhov sib txawv ntawm FeSO4. (e) Oxidative kev nyuaj siab tsom xam ntawm qus-hom thiabsnf1 ua∆ Cov kab mob incubated nrog ntau qhov sib txawv ntawm FeSO4. (f) CLS tsom xam ntawm cov tsiaj qus thiabsnf1 ua∆ Cov kab mob incubated nrog ntau qhov sib txawv ntawm FeSO4. Statistical tseem ceeb (*p < 0.05) was determinedlos ntawm Tub Kawm Ntawvt- kuaj.
Txij li thaumsnf1 uamutant muaj qhov tsis xws luag hauv mitochondrial zog, peb tau sim seb puas muaj cov hlau ntxiv tuaj yeem cawm cov phenotypes nrawm nrawm. Yog li ntawd, peb ntxiv cov hlau rausnf1 uamutant thiab soj ntsuam ATP qib, oxidative kev nyuaj siab, thiab lifespan. Peb pom tias cov hlau ntxiv tau nce qib ATP, tiv thaiv oxidative kev nyuaj siab, thiab kev ua neej nyob (Daim duab5d-f). Ua ke, cov kev tshawb pom no tau lees paub tias cov hlau txuas ntxiv ncua kev laus thiab txuas ntxiv cellular lifespan los ntawm kev ua haujlwm ntawm mitochondria.
4. Kev sib tham
Cov khoom noj khoom haus txiav txim siab txog kev ua haujlwm ntawm cov hlwb thiab qhov tsis txaus ntawm cov as-ham tseem ceeb cuam tshuam rau tib neeg kev noj qab haus huv [55,56]. Tsis tas li ntawd, cov as-ham yog lub luag haujlwm tseem ceeb ntawm cov metabolism hauv cellular uas tswj ntau cov txheej txheem lom neeg suav nrogkev laus, ib qho kev pheej hmoo loj ntawm ntau yamkab mob ntev. Ib tug poob rau hauvkev ua haujlwm metabolicyog ib lub cim ntawmkev laus [10]. Kev tshawb fawb tsis ntev los no hauv cov kab mob sib txawv, suav nrog cov tsiaj nyeg, tau pom tias kev ncua kev laus thiab kev noj qab haus huv muaj peev xwm ua tau los ntawm kev tiv thaiv kev laus xws li rapamycin thiab kev tswj hwm tshuaj metformin [11,16]. Cov tshuaj no tsom rau cov khoom noj khoom haus-sensing complexes TORC1 thiab AMPK uas yog cov tseem ceeb metabolic regulators ntawm cov hlwb [11,16].
Hlau yog ib qho tseem ceeb ntawm cov khoom noj uas muaj feem xyuam nrog ntau yam tseem ceeb hauv cov txheej txheem metabolic hauv cov hlwb [23–26]. Iron deficiency impairs metabolic kev ua ub no ua rau muaj kev cuam tshuam ntawm cellular functions, ua rau ntau yam kab mob, xws li anemia, paub tsis meej, thiab poob ntawmcov leeg muaj zog [26,57–59]. Iron deficiency yog dav dav hauv cov neeg laus lausNtau dua lossis sib npaug65 xyoo [60–62].
Txij li cov hlau tswj cov txheej txheem metabolic, peb tshawb xyuas nws lub luag haujlwm hauv kev laus. Peb siv cov poov xab ua qauv kab mob los tshuaj xyuas lub luag haujlwm ntawm cov hlau hauv kev laus raws sijhawm. Peb tshawb xyuas cov txiaj ntsig ntawm cov hlau ntxiv rau CLS ntawm cov poov xab. Peb pom tias ob qho tib si FeSO4 thiab FeCl3 nce cellular lifespan. Siv cov ntsev sib txawv ntawm sulfate, chloride, thiab hlau chelator, peb paub tseeb tias lub cellular lifespan yog txuas ntxiv los ntawm hlau. Kev laus muaj feem cuam tshuam nrog kev nce zuj zus ntawm oxidative kev nyuaj siab, uas ua rau muaj kev phom sij rau cellular zog thiab txo qis cell ciaj sia [34]. Txij li thaum peb pom tias cov hlau supplementation ncua kev laus, peb sim seb nws puas tuaj yeem muab kev tiv thaiv oxidative kev nyuaj siab. Txhawm rau tshuaj xyuas oxidative stress phenotype, peb kho cov hlwb nrog oxidative inducer tus neeg sawv cev H2O2 thiab ntsuas lub cell ciaj sia. Peb pom tias hlau supplementation nce oxidative kev nyuaj siab piv rau kev tswj. Cov kev tshawb pom no cuam tshuam nrog lub luag haujlwm ntawm cov hlau ntxiv hauv kev txuas ntxiv ntawm kev ua neej.
Peb ntxiv unraveled lub anti-aging mechanism ntawm hlau supplementation. Mitochondria yog cov neeg siv xov tooj tseem ceeb ntawm kev siv hlau thiab cov metabolism [35–38]. Peb thawj zaug txheeb xyuas qhov kev qhia ntawm mitochondrial TCA cycle noob. Peb pom tias qhov kev qhia ntawm yuav luag tag nrho TCA lub voj voog cov noob tau raug kho los ntawm kev ntxiv hlau. Qhov tseem ceeb, cov hlau supplementation downregulated qhia ntawm mitochondrial anaplerosis thiab upregulated cataplerotic metabolic noob. Cov txiaj ntsig no qhia tau hais tias kev siv hlau ntxiv txhim kho cov synthesis ntawm TCA lub voj voog nruab nrab thiab tiv thaiv lawv txoj kev siv cellular. Cov kev tshawb pom no txhawb kev tiv thaiv kev laus ntawm cov hlau ntxiv, raws li kev xa tawm ntawm TCA lub voj voog nruab nrab cuam tshuam rau mitochondrial kev ncaj ncees [47]. Ntxiv mus, ntxiv cov pa roj carbon mitochondrial yog qhov tseem ceeb los tswj cov haujlwm mitochondrial uas xav tau kom muaj sia nyob thaum lub sijhawm laus ntawm tes.
TCA lub voj voog nruab nrab -ketoglutarate tau pom tias txuas ntxiv lub neej ntawm cov kab mob sib txawv [63]. Txawm li cas los xij, peb pom tias cov hlau supplementation nce qhov kev qhia ntawm - ketoglutarate dehydrogenase,KGD 1thiabKGD 2) uas converts - ketoglutarate los tsim succinyl-CoA. Ntxiv mus, peb tau pom tias qhov kev qhia ntawm succinate dehydrogenase noob (SDH1thiabSDH 2) tau hloov kho siab ntawm lwm cov noob caj noob ces ntawm TCA lub voj voog. Qhov tseem ceeb, succinate dehydrogenase koom nrog hauv TCA lub voj voog thiab ETC complex II. Cov txiaj ntsig no tau qhia tias es tsis txhob sib sau ib qho TCA lub voj voog nruab nrab, qhov kev tiv thaiv kev laus ntawm cov hlau ntxiv tuaj yeem koom nrog ETC txoj hauv kev.
Txij li thaum TCA lub voj voog ua haujlwm txuas nrog ETC, peb tau txheeb xyuas qhov kev qhia ntawm ETC noob. Peb pom tias cov khoom siv hlau ntxiv tau txhawb nqa kev qhia ntawm ETC cov noob. TCA cycle khoom NADH thiab FADH2 yog oxidized los ntawm ETC complexes thiab tsim ATP los ntawm OXPHOS. Peb pom tias cov hlau supplementation nce qib cellular ATP, uas cuam tshuam nrog kev txhawb nqa ntawm TCA lub voj voog thiab ETC noob. Tom ntej no, peb elucidated seb qhov nce ntawm ATP qib los ntawm kev ntxiv hlau yog xav tau rau kev ncua ntawm cellular lifespan. Peb pom tias lub neej ncua ntev los ntawm kev ntxiv hlau tau raug tshem tawm los ntawm inhibiting ATP synthesis. Yog li, cov fifindings no qhia tias cov hlau supplementation nce qib ntawm ATP uas yuav tsum tau rau kev ncua ntawm cellular lifespan. Peb cov txiaj ntsig tau zoo ib yam nrog cov ntaub ntawv dhau los uas qhia txog lub luag haujlwm ntawm ATP hauv cellular lifespan [51,64,65]. Tsis tas li ntawd, peb tau siv hlau ntxiv los txhim kho mitochondrial zog thiab cawm lub neej luv luv thiab oxidative kev nyuaj siab-rhiab phenotype ntawm AMPK mutant. Ua ke, cov txiaj ntsig no tau qhia tias kev ntxiv cov hlau muaj peev xwm ua rau cov haujlwm mitochondrial uas ncua kev laus thiab ua kom lub neej ntev ntawm cov hlwb.
Cov kev tshawb fawb tsis ntev los no tau pom tias cov hlau ntxiv rov qab kho qhov tsis xws luag mitochondrial ntawm lysosome-tsis muaj zog mutants thiab tiv thaiv mitochondrial poob qis thaum laus [66,67]. Yog li, peb cov txiaj ntsig tau txhawb nqa qhov kev tshawb pom yav dhau los uas cov hlau ntxiv txhim kho mitochondrial zog. Interestingly, ib qho ntawm cov kev tshawb fawb yav dhau los qhia tau hais tias cov hlau supplementation cawm tau qhov kev rov ua dua ntawm kev laus ntawm lysosome-tshuaj mutants; txawm li cas los xij, covcuam tshuam rau cov tsiaj qus hom tsis tau suav nrog hauv tsab ntawv ceeb toom [67]. Txawm li cas los xij, peb cov txiaj ntsig tau cuam tshuam nrog cov kev tshawb pom yav dhau los, thiab txawm tias muaj cov qauv kev laus sib txawv (kev laus laus), peb pom tias cov hlau supplementation ncua kev laus thiab nce cellular lifespan. Yog li, sib sau ua ke, peb cov txiaj ntsig thiab cov ntaub ntawv dhau los tau qhia meej tias kev ntxiv cov hlau tuaj yeem yog qhov kho tau zoo rau lub hom phiaj kev laus thiab nce kev noj qab haus huv.
Cov khoom siv ntxiv:Daim duab S1: Kev loj hlob thiab kev soj ntsuam lub neej ntev ntawm cov hlau-cov poov xab ntxiv; Daim duab S2: Kev soj ntsuam kev loj hlob ntawm cov hlau sib txawv, sulfate, thiab chloride-muaj cov ntsev ntxiv-cov poov xab ntxiv; Daim duab S3: Oxidative stress resistance analysis of iron-supplemented poov cells. Daim duab S4: Mitochondrial gene qhia, daim nyias nyias muaj peev xwm, thiab cov qauv kev tsom xam ntawm cov hlau-cov poov xab ntxiv; Daim duab S5: Kev tsom xam kev loj hlob ntawm cov hlau thiab antimycin A-suppleted poov hlwb; Table S1: Daim ntawv teev cov primers siv rau RT-PCR hauv txoj kev tshawb no.
Tus sau kev koom tes:JLJ: Txoj Kev, Kev Tshawb Fawb, Kev Tshawb Fawb, thiab Kev Ntsuam Xyuas; TCYN: Cov txheej txheem, kev txheeb xyuas, kev tshawb nrhiav, thiab tshuaj xyuas; FN: Kev lees paub, kev tshuaj xyuas, thiab tshuaj xyuas; FE: Kev tshuaj xyuas, kho, thiab saib xyuas; MA: Conceptualization, Data curation, Methodology, Writing, Reviewing, Editing, and Supervision. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:Txoj haujlwm no tau txais kev txhawb nqa los ntawm Bioinformatics Institute (BII), A*STAR Career Development Fund (C210112008), thiab Global Healthy Longevity Catalyst Awards grant (MOH-000758-00).
Kev lees paub:Peb ua tsaug rau Maurer-Stroh Sebastian, Lee Hwee Kuan, Loo Lit Hsin, Chiam Keng Hwee, thiab Prakash Arumugam rau kev txhawb nqa qhov kev tshawb fawb no.
Kev tsis sib haum xeeb ntawm kev txaus siab:Cov kws sau ntawv tshaj tawm tsis muaj kev sib tw nyiaj txiag thiab tsis yog nyiaj txiag txaus siab.
Cov ntaub ntawv
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