Sirtuins Modulation: Lub Tswv Yim Zoo Tshaj Plaws Rau HIV-Associated Neurocognitive Impairments Part 2
Jun 11, 2024
Interestingly, Campestrini et al. [23] pom tias mRNA ntawm Bcl-2 qib tau nce ntxiv tom qab 72 h Tat-kho tib neeg T lymphocyte cell kab (Jurkat). Txawm li cas los xij, lawv tau siv HIVTat clade C, uas muaj qhov hloov pauv R57S piv rau clade B thiab cuam tshuam nrog cell uptake ntawm Tat [50].
Lymphocytes yog ib qho tseem ceeb ntawm lub cev tiv thaiv kab mob hauv tib neeg lub cev, lub luag haujlwm rau kev tawm tsam ntawm ntau yam kab mob thiab kab mob. Tib neeg kev nco yog lub peev xwm ntawm tib neeg lub hlwb kom nco qab thiab nco qab cov ntaub ntawv. Puas yog ob qho tsis sib xws? Muaj qee qhov kev sib txuas ntawm lymphocytes thiab nco.
Cov kev tshawb fawb tau pom tias thaum peb ntsib qee yam xwm txheej lossis raug cuam tshuam rau qee yam stimuli, lub cev tiv thaiv kab mob yuav pib muaj kev cuam tshuam ntau, suav nrog kev ua haujlwm ntawm lymphocytes. Hauv cov txheej txheem no, lymphocytes tsim cov tshuaj hu ua cytokines, uas tuaj yeem cuam tshuam rau kev ua haujlwm ntawm lub paj hlwb. Qhov no txhais tau hais tias kev ua haujlwm ntawm lymphocytes tuaj yeem txhawb kev sib txuas ntawm cov neurons hauv tib neeg lub cev thiab txhim kho kev cia thiab rov nco qab.
Tsis tas li ntawd, T lymphocytes hauv lymphocytes tseem tuaj yeem koom ncaj qha rau hauv lub cev tiv thaiv kab mob ntawm lub hlwb kom tiv thaiv cov kab mob los ntawm kev nkag mus thiab ua rau muaj kev mob tshwm sim. Qhov kev tiv thaiv no tseem ceeb heev rau kev noj qab haus huv ntawm tib neeg lub hlwb thiab kev saib xyuas kev nco. Tom qab rov ua dua cov kab mob tib yam, T lymphocytes yuav maj mam tsim kev nco, yog li lub sij hawm tom ntej ntawm cov kab mob tau ntsib, tib neeg lub cev tuaj yeem teb sai dua rau lub cev tiv thaiv kab mob, yog li txo qhov tshwm sim ntawm kev kis kab mob.
Yog li ntawd, kev tiv thaiv kev noj qab haus huv ntawm lymphocytes thiab tswj kev ua haujlwm ntawm lub cev tiv thaiv kab mob tuaj yeem tswj hwm lub cev tiv thaiv kab mob, tswj lub cev kev noj qab haus huv, thiab tseem ceeb tshaj, txhim kho kev nco. Noj qab nyob zoo, pw tsaug zog txaus, ntxiv dag zog rau kev tawm dag zog, thiab ua kom lub siab zoo siab yog txhua txoj hauv kev los txhim kho lymphocytes thiab nco. Nco ntsoov tuav tus cwj pwm zoo thiab ua kom koj lub cev, lub hlwb, thiab lub cev tsis muaj zog. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche muaj cov tshuaj tiv thaiv antioxidant, tiv thaiv kev laus, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv kev noj qab haus huv. paj hlwb. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm muaj peev xwm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv qhov tshwm sim ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.
Nyem paub txoj hauv kev los txhim kho lub hlwb
Tsis tas li ntawd, ntau cov ntaub ntawv qhia txog qhov sib txawv ntawm cov teebmeem ntawm tes ntawm clade B thiab C, nrog rau qhov kawg tsis tshua muaj neurotoxic [72]. Yog li ntawd, ib nrab mitochondrialdamage raug pom zoo, los yog ib qho tsis tiav MOMP qhov twg cov mitochondria tsis muaj kev puas tsuaj qhia txog qib BCL-2 [54], tab sis cov kev tshawb fawb ntxiv yuav tsum tau lees paub qhov kev xav no.
Hloov pauv, ER kev ntxhov siab tau pom nyob rau hauv txoj hauv kev apoptotic, uas muab rau hauv UPR [23]. Lub ER feem ntau paub txog nws txoj haujlwm ntawm cov protein ntau, folding, thiab maturation.
ER kev ntxhov siab tau txais thaum qhov kev txhawb nqa ua rau muaj kev hloov pauv hauv cov txheej txheem ua haujlwm protein, ua rau cov protein tsis sib xws lossis tsis raug. Txhawm rau tiv thaiv kev ua haujlwm tsis zoo, ERtriggers UPR qhov twg cov teeb liab cascades tau qhib kom rov tsim kho cov protein ntau, cov protein hloov mus rau ER, thiab autophagy, los kho cov proteostasis lossis induceapoptosis yog ER homeostasis tsis ncav cuag.
Txoj hauv kev koom nrog UPR yog ua los ntawm daim nyias nyias ER proteins PERK, IRE1a, thiab ATF6a. PERK phosphorylates eukaryotictranslation pib qhov tseem ceeb 2 subunit- (eIF2) yog li protein synthesis thiab unfolded proteininflux tuaj yeem txo.
eIF2 induces kev txhais ntawm ATF4 mRNA, uas nkoos geneexpression ntawm cov proteins uas yuav tsum tau rau txo-oxidation tshuav nyiaj li cas; autophagy; thiab apoptosiss xws li CCAAT/enhancer-binding protein homologous protein (CHOP), kev loj hlob raug ntes, thiab DNA puas-inducible protein (GADD34).
CHOP tswj hwm GADD34, uas nyob rau tib lub sijhawm modulates tuag receptor 5 (DR5), uas recruits caspase 8 rau cleavage-mediatedactivation ntawm BID, ib qho ntawm cov pro-apoptotic proteins nyob rau hauv txoj kev mitochondrial tham saum toj no [73].
Lwm txoj hauv kev taw qhia yog ib qho tswj hwm los ntawm IRE1 kev sib cais los ntawm GRP78 thiab nws txoj haujlwm RNase ua kom. Tom qab ntawd, IRE1 lub hom phiaj ntawm mRNA ntawm X-box-bindingprotein 1 (XBP1), tshem tawm ib qho 26-nucleotide intron uas tso cai rau kev nthuav tawm ntawm daim ntawv qhib ntawm XBP1.
Cov protein no yog kev tswj hwm ntawm lwm cov noob muaj feem xyuam nrog kev sib tw, kev tso tawm, thiab tshem tawm cov proteins tsis zoo. Tsis tas li ntawd, IRE1 tuaj yeem dhau los ua cov txheej txheem tswj hwm IRE1-dependent decay (RIDD), qhov twg mRNAs raug degraded, suav nrog DR5, ib qho kev tiv thaiv apoptotic mechanism. Txawm li cas los xij, cov xwm txheej ntawm kev ntxhov siab ntev ntev txo RIDD cov txiaj ntsig, ua rau cov cell tuag.
Thaum kawg, ATF6 cascade pib nrog nws txoj kev thauj mus rau Golgi apparatus thiab cleavage tso tawm ib feem ntawm ATFp50, uas translocates mus rau lub nucleus thiab induces gene qhia nyob rau hauv ib tug zoo xws li txoj kev uas XBP1 tab sis nrog qhov sib txawv uas ATFp50 kuj modulates Golgi apparatus biogenesis [73].
Nyob rau hauv cov ntsiab lus no, nws tau raug tshaj tawm tias Tat-induced ER kev ntxhov siab ua rau unfolded protein teb (UPR) ua kom pom los ntawm cov noob qhia nce ntawm IRE1, PERK, thiab ATF6, thiab tib lub sijhawm, kos npe tau pom ntawm mitochondrial dysfunction kho los ntawm kev poob. ntawm mitochondrial membrane muaj peev xwm thiab caspase 12 thiab caspase 3 ua kom [23].
Tsis tas li ntawd, nyob rau hauv tib neeg lub hlwb, microvascular endothelial hlwb Tat-exposure cuam tshuam nrog nce protein ntau ntau ntawm IRE1, PERK, ATF6, thiab Bip / GRP78, uas ua rau ROSincrease [70].
Cells raug kev txom nyem los ntawm Ca2+ influx nce los ntawm Tat cuam tshuam nrog N-methyl-Daspartate receptor (NMDAR) [63]. Txawm li cas los xij, cov tswv yim los thaiv cov receptor no ua tsis tiav los txo HAND [74], qhia tias Tat siv lwm txoj hauv kev los cuam tshuam Ca2+homeostasis. Ca2+ khaws cia hauv ER hauv ib txwm muaj, thiab nws qhov kev tso tawm yog hloov kho los ntawm kev sib txawv stimuli.
Tsis ntev los no, cov ntaub ntawv pov thawj tau qhia tias ob qho tib si ER thiab mitochondria sib cuam tshuam los ntawm ib txoj hauv kev hu ua mitochondria-associated ER membranes, qhov twg cov txheej txheem cellular tshwm sim, suav nrog Ca2+ thauj thiab induction rau cell tuag thaum lub sij hawm ntev cellularstress [75].
Ca2+ signaling yog qhov kev pom zoo tshaj plaws ntawm ob lub cev, nrog kev pab ntawm IP3 receptors [76]. ER-mitochondria kev sib txuas lus zoo li yog lub voj voog tawm tswv yim.
Nce cytosolic Ca2+ ntau ntau vim ER kev ntxhov siab-kho kev tso tawm provoke cuam tshuam hauv mitochondrial membrane muaj peev xwm, ua rau muaj kev nce hauv ROSproduction. ER kev ntxhov siab tuaj yeem raug ntxias los ntawm cov txheej txheem kev loj hlob ntawm cov protein tsis zoo uas tshwm sim los ntawm qib siab ntawm mtROS.
Tsis tas li ntawd, mitochondrial Ca2+ uptake induces qhov qhib ntawm permeability hloov pore (mPTP) thiab tso tawm ntawm cytochrome c, uas tsav activation ntawm caspases [75], qhia tias Ca2+ signaling ntawm ER thiab mitochondria tswj cellular respiration. Yog li, qhov nce hauv cytoplasmatic Ca2+ concentration tuaj yeem ua rau cell demise.
Kev soj ntsuam hauv Tat-exposed embryonic nas hippocampal neurons pom qhov nce hauv cytosolic Ca2+ thiab mitochondrial uptake, uas ua rau cov membrane depolarization thiab cell tuag [64].
Tat-induced intracellular Ca2++ nce yog tus cwj pwm los ntawm qhov pib hloov pauv theem IP3- kho kom haum xeeb thiab lub sijhawm ntev thib ob uas cuam tshuam los ntawm NMDARsin fetal tib neeg lub hlwb neurons [77] thiab cov hloov pauv hloov pauv muaj peev xwm canonical channelin nas Nacc neurons [ 74] uas ua rau cell tuag.
Cov kev tshawb pom no tau lees paub tias Tat cuam tshuam rau kev sib txuas lus ntawm mitochondria-ER los ntawm dysregulation ntawm Ca2+ homeostasis thiab imbalance ntawm pro thiab anti-apoptotic proteins, ua rau mitochondrial dysfunction, uas inturn provokes apoptosis.
Raws li tau hais ua ntej, kev sim tshuaj kho mob tau ua tiav los daws Tat-mediated Ca2+ dysregulation siv NMDAR antagonists yam tsis muaj cov txiaj ntsig tseem ceeb cuam tshuam rau kev nce qib ntawm HAND [74]. Yog vim li cas tom qab cov txiaj ntsig no yuav yog qhov tseeb tias calcium dysregulation tsuas yog ib qho ntawm Tat-mediated teebmeem, uas yog tshwm sim los ntawm ntau qhov xwm txheej.
Yog li ntawd, ib lub tswv yim yuav yog los daws ib qho kev tshwm sim uas feem ntau ntawm txoj kev cuam tshuam kev sib tshuam thiab yog qhov tseem ceeb rau neurodegeneration, xws li mitochondrial dysfunction, thiab daws nws cov regulator molecules xws li sirtuins.
5. Sirtuins
Sirtuin1–7 yog ib feem ntawm tsev neeg ntawm cov proteins chav kawm III histones deacetylases. Tag nrho SIRTsare NAD+- nyob ntawm cov enzymes thiab koom nrog ntau yam xwm txheej ntawm tes xws li kev tsim cov noob caj noob ces, kho DNA, thiab kev laus [78].
Lawv nthuav tawm ntau yam kev ua haujlwm thiab kev faib tawm ntawm tes vim yog qhov sib txawv ntawm cov qauv hauv N- thiab C-terminal. Kev txuag catalyticcore ntawm SIRTs muaj ob lub subdomains: Rossmann-fold thiab zinc-binding domain.
Substratesand NAD + khi rau lub active cleft ntawm ob subdomains. Kev sib cuam tshuam ntawm cov tub ntxhais catalytic, substrate, thiab NAD + induces ib tug conformational hloov uas ua rau activecleft kaw [79].
Cov kev ua haujlwm zoo catalytic yog lysine deacetylation, tab sis ntau qhov kev sim tau xaus tias SIRT5 tuaj yeem tshem tawm cov succinyl thiab malonyl pawg thiab SIRT4 yog ib qho ADP-ribosyltransferase [80].SIRT1 thiab SIRT2 muaj nyob rau hauv cov nucleus thiab cytoplasm, thaum SIRT3 yog lub ntsiab . Qhov tseeb, qhov no pab txwv tsis pub lawv cov substrates txij li SIRTs tsis pom qhov nyiam hauv cov protein ntau.
Txawm li cas los xij, acetyllysine residue yuav tsum nyob hauv ib lub voj-helices kom nkag mus rau cov tshuaj tiv thaiv deacetylation [80]. Txawm hais tias qhov pom tseeb ntawm substratenon-qhov tshwj xeeb ntawm SIRTs, nws tau tshaj tawm tias tsuas yog SIRT1, SIRT2, thiab SIRT3 tuaj yeem deacetylateTat [31], uas ua pov thawj kev sib cuam tshuam ncaj qha uas tuaj yeem ua rau muaj kev hloov pauv hauv SIRTs ua haujlwm rau lwm cov substrates.
Yog li ntawd, nyob rau hauv qhov kev tshuaj xyuas no, peb them sai sai rau cov lus hais saum toj no peb lub molecules, thiab SIRTs-tswj txoj hauv kev tau qhia hauv daim duab 2.
5.1. Sirtuins hauv Cov Kab Mob Neurodegenerative
Sirtuins 1-7 yog qhia nyob rau hauv lub hlwb ntawm txawv degrees. SIRT1 thiab SIRT2 yog qhov nquag tshaj plaws hauv cov ntaub so ntswg, tab sis SIRT1 tau qhia ntau heev hauv cov neurons, thaum SIRT2 muaj ntau hauv oligodendrocytes.
Cov sirtuins 3–5 yog pawg thib ob uas pom nyob rau hauv lub hlwb, thiab qhov tsawg tshaj plaws yog SIRT6-7. SIRT1 feem ntau nyob ntawm lub hauv paus, thiab SIRT2 yog faib rau hauv cytoplasm, thaum SIRT3 yog los ntawm kev nyiam abundantin mitochondria tab sis nrog qee cov isoforms nyob hauv cytoplasm thiab nucleus [81]. SIRTexpression txawv nyob ntawm lub hlwb, hnub nyoog, thiab cov kab mob pathological thiab tau muaj feem xyuam rau cov kab mob neurodegenerative xws li PD thiab AD.
PD pathogenesis yog tus cwj pwm los ntawm kev sib sau ntawm -synuclein, uas tuaj yeem txo qis hauv nas hlwb PD qauv ua rau SIRT1 overexpression [82]. Txawm li cas los xij, inhibition ntawm SIRT2 mitigates -synucleintoxicity hauv tib neeg neuroglioma hlwb [83].
Ntawm qhov tod tes, SIRT1, SIRT3, thiab SIRT6 qhia tau txo qis hauv lub hlwb ntawm cov neeg mob AD [84]. Ntxiv mus, SIRT1 [85] thiab SIRT3 [86] cov protein ntau tau txo qis hauv cerebral cortex ntawm cov tib neeg nrog AD.Ob SIRT1 thiab SIRT3 dysregulation tau cuam tshuam nrog kev paub txog kev ua haujlwm [85,87].
5.2. SIRT 1
SIRT1 koom nrog ntau cov txheej txheem ntawm tes, suav nrog cell metabolism, kho DNA, mitochondrial biogenesis, apoptosis [88,89], circadian timing system [90], gene silencingthrough kev cuam tshuam nrog DNA methyltransferase 1 [91], heterochromatin tsim [92], cell Lub voj voog kev loj hlob [93], thiab oxidative kev nyuaj siab teb [94].
Vim muaj kev sib cuam tshuam nrog ntau cov molecules, SIRT1 tau nyiam nws lub luag haujlwm hauv ntau yam kab mob, suav nrog mob qog noj ntshav [95], ntshav qab zib hom 2 [96], thiab cov kab mob neurodegenerative [97,98].
5.2.1. SIRT1 hauv ER Stress thiab UPR
Tsis ntev los no, kev tshawb pom tau qhia tias SIRT1 ua lub luag haujlwm tseem ceeb hauv ER kev ntxhov siab mitochondria apoptotic txoj kev tswj hwm [27,99,100]. Hauv thawj chondrocytes, pharmacological thiab genetic inhibition ntawm SIRT1 ua rau phosphorylated PERK nce thiab qis cov proteins xws li eIF-2 thiab CHOP [27]. Ib yam li ntawd, nyob rau hauv lub plawv hlwb, depletion ntawmSIRT1 nce protein ntau ntawm phosphorylated eIF-2 , ATF4, GADD34, thiab CHOP [99].
Txawm li cas los xij, overexpression lossis activation ntawm no sirtuin ua rau abrogation ntawm cell tuag nyob rau hauv ob txoj kev kawm. Tsis tas li ntawd, kev nce hauv acetylated cov ntaub ntawv ntawm ob qho tib si PERK [27] thiab eIF-2 [99] raug soj ntsuam. Txawm li cas los xij, Ghosh et al. [100] tau tshaj tawm tias txawm tias tsis muaj ER kev ntxhov siab, SIRT1 depletion koom nrog PERK UPR ceg ua haujlwm los ntawm kev tswj hwm qib ntawm phosphorylated eIF-2 ; Tsis tas li ntawd, lawv pom cov pov thawj ntawm kev sib cuam tshuam ntawm lub cev ntawm SIRT1, CHOP, thiab GADD34 [100] tom qab tau lees paub los ntawm cov pov thawj pom kev tsim cov anarsenite-induced Sirt1/GADD34/PP1/eIF-2 complex thiab nuclear SIRT1 translocation tocytoplasm, uas ua rau GADD34-mediated dephosphorylation/deacetylation ntawm eIF-2 thiab dephosphorylation ntawm SIRT1 [101]. Ua ke, cov ntaub ntawv no qhia tias SIRT1 tuaj yeem ua tus tswj hwm ntawm apoptosis; yog li ntawd, qhov nyuaj GADD34/PP1 yog ib tug repressor ofeIF-2 , ua rau lub restoration ntawm ER muaj nuj nqi thaum cellular stress tau daws [73].
Ntxiv mus, nws tau raug pom tias lub luag haujlwm ntawm SIRT1 hauv cell proliferation yog kho los ntawm nws qhov chaw [102], uas kuj yog nyob ntawm hom cell [103]. Txawm li cas los xij, nws yog qhov yuav tsum tau tshem tawm cov txheej txheem uas hom cell siv tawm tsam ntau hom kev ntxhov siab thiab cov lus teb them nyiaj uas tau qhib.
5.2.2. SIRT1 thiab Mitochondrial Dysfunction
Mitochondria dysfunction tshwm sim los ntawm kev cuam tshuam hauv lawv cov kev ua haujlwm metabolic thiab nquag, nrog rau kev tsis txaus ntseeg hauv lawv cov xwm txheej tswj kom zoo, suav nrog organellefission-fusion, mitochondrial biogenesis, thiab mitophagy.
Lub zog ntawm fusion thiab fission yog qhov tseem ceeb rau kev hloov pauv ntawm tes thiab kev faib cov organelle raws li ntau yam mob, xws li mitophagy thiab mitochondria biogenesis [104]. SIRT1 tswj mitochondrialbiogenesis los ntawm ntau qhov kev cuam tshuam deacetylation.
Lub serine/threonine-protein kinaseSTK11 (LKB1) yog qhib los ntawm SIRT1, ua rau phosphorylation ntawm AMP-activated protein kinase (AMPK). Tom qab ntawd, FOXO3 yog phosphorylated thiab deacetylated los ntawm SIRT1 topromote transcription ntawm PGC1 , uas induces transcription ntawm nuclear transcription yam (Nrf1-2) thiab transcription factor A (TFAM), uas muaj feem xyuam rau mtDNA replication thiab transcription [28].
Paradoxically, SIRT1 tau cuam tshuam nrog mitophagy, tab sis cov txheej txheem ntxaws tseem raug txiav txim siab. Qee cov kev tshawb fawb tau qhia tias cov activators xws li resveratrol (RV) thiab SRT1720 induce mitophagy los ntawm transcriptional induction ntawm PINK1through FOXO3 SIRT1-mediated acetylation [105,106].
Tsis tas li ntawd, SIRT1 yuav tsum muaj rau mitochondrial fragmentation los ntawm kev ua raws li cytoskeleton hauv cov ntsiab lus ntawm Ca2+dysregulation [107]. Cov kev tshawb pom no ua pov thawj qhov tseeb tias SIRT1 yog qhov tseem ceeb ntawm kev hloov pauv hauv kev ua haujlwm tsis zoo hauv mitochondrial.
5.2.3. SIRT1 thiab Tat
Hauv kev kis kab mob HIV, SIRT1 yuav tsum tau ua rau Tat Lys50 deacetylation txij li Tat-trans-actingresponsive element (TAR) complex formation tsuas yog siv rau hauv nws daim ntawv tsis muaj acetylated, tab sis Tat acetylation yuav tsum tau mus txuas ntxiv nrog cov ntawv sau.
Thaum cov txheej txheem tiav lawm, tib lub Tat molecules tuaj yeem rov ua dua los ntawm SIRT1-deacetylation los pib dua lwm TAR complex [31,108]. Interestingly, SIRT1-Tat kev sib cuam tshuam yog ywj siab ntawm Tat acetylationstate [31], uas qhia tias Tat-induced SIRT1 inhibition tshwm sim thaum Tat rov ua dua tsis xav tau [108].
Txawm li cas los xij, muaj qee cov lus nug txog qhov inhibition mechanisms vim nws tsis paub meej yog tias cov txheej txheem allosteric tau tshwm sim thiab yog tias muaj qhov concentration ntawm qhov inhibition.
Txawm li cas los xij, nws tseem ceeb heev uas Tat-induced SIRT1 inhibition ua rau hyperactivation ntawm T hlwb [30]. Raws li tus neeg ua si hauv nruab nrab hauv ntau cov txheej txheem ntawm tes, Tat-mediated SIRT1 inhibition tuaj yeem koom nrog hauv cell dysregulation uas nyob rau hauv lem ua rau neuronal poob. Yog li ntawd, kev ua kom lub sirtuin no yuav tsum tau txiav txim siab los tuav tes.
5.3. SIRT 2
Txawm hais tias SIRT2 concentrations siab dua hauv cytosol, thaum lub sij hawm lub voj voog ntawm tes G2 / Mtransition lawv tau hloov mus rau lub nucleus, qhov chaw lawv tswj hwm H4K20 methylation bydeacetylation ntawm histone H4K16, uas yog qhov tseem ceeb hauv chromosome compaction [109].
Paradoxically, muaj pov thawj ntawm cell proliferation cuam tshuam thiab cell voj voog ntes nyob rau hauv overexpressingSIRT2 ntsws cancer hlwb [110]. Hauv cytoplasm, SIRT2 cuam tshuam nrog -tubulin, uas yog ib feem ntawm cytoskeleton. Cov qib acetylation sib raug zoo nrog microtubule ruaj khov, thiab hauv SIRT2-cov kab mob cerebellar granule ntau dhau ntawm cov nas Wallerian degeneration qeeb, cuam tshuam ntawm hyperacetylation thiab tiv thaiv axonal degeneration tau pom [111].
Txawm li cas los xij, nws tau pom tias SIRT2-/- nas ua rau axonal kev puas tsuaj nrog rau qhov qis glutathionelevels txo ATP, txo mtDNA concentration, thiab ua rau muaj kev qhia siab ntawm SIRT1 piv rau hom tsiaj qus [112], qhia txog kev cuam tshuam ntawm mitochondria homeostasis.
Raws li cov txiaj ntsig no, Liu et al. [113]. pom tias nyob rau hauv striatum SIRT2-/- nas hlwb, ob peb mitochondrial proteins muaj acetylation ntau dua WT, nrog rau cov koom nyob rau hauv lub zog tsim. Qhov ua tau tias SIRT2 ua haujlwm hauv mitochondria kuj tau lees paub hauv tib pab pawg txij li SIRT2 tuaj yeem nyob hauv thaj chaw mitochondria ntawm Wt nas hlwb thiab murine embryonic fibroblasts [113].
Tsis tas li ntawd, SIRT2-/- nas cortex qhia tau hais tias depletion ntawm no sirtuin ua rau mitochondrial hloov loj, nce qib ntawm acetylated PGC1, thiab downregulation ntawm kev qhia ntawm mitochondrial fusion-txog noob Mfn1, Mnf2, thiab Opa1. [113]. Hloov pauv, nyob rau hauv kev ntxhov siab, HepG2SIRT2-Wt hlwb txo DRP1; lub caij no, SIRT2-catalytic inactivated hlwb tsis tau [114].
Nyob rau hauv cov ntsiab lus ntawm oxidative kev nyuaj siab, SIRT2 overexpression nce cell viability thiab induces FOXO3a-mediated SOD2 qhia nyob rau hauv neuroblastoma hlwb [115]. Ntawm qhov tod tes, SIRT2-/- MFs tau pom qhov nce ntxiv hauv ROS thiab mitophagy tseem ceeb regulator proteins, PINK1, thiab parkin, nrog rau LC3B, tus tsim rau kev puas tsuaj mitochondriaclearance [113].
Cov teebmeem neuroprotective discrepancies ntawm SIRT2, uas tej zaum yuav yog qhov tshwm sim ntawm ntau cov lus teb rau lub cell siv nyob rau hauv txawv stimuli.Txawm li cas los xij, lub luag haujlwm ntawm SIRT2 hauv mitochondrial homeostasis yog qhov tseem ceeb.
Qhov tseeb tias Tat lub cev cuam tshuam nrog cov sirtuin no thiab qhov cim ntawm Tat-induced neurotoxicityis mitochondrial dysfunction tuaj yeem ua rau peb xav txog qhov kev hloov pauv tau zoo ib yam li SIRT1. Yog li, kev tshawb nrhiav yav tom ntej yog qhov tsim nyog los txiav txim siab txog kev sib raug zoo ntawm SIRT2 thiab Tat.
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