Lub luag haujlwm ntawm EIF5A hauv Mitochondrial Function

Thov hu rauoscar.xiao@wecistanche.comyog xav paub ntxiv

Abstract:Lub eukaryotic txhais lus pib qhov tseem ceeb 5A (eF5A) yog ib qho evolutionarily conserved protein uas khi ribosomes los pab txhawb kev txhais ntawm peptide motifs nrog sib law liag prolines los yog ua ke ntawm prolines nrog glycine thiab them cov amino acids. Nws kuj tau txuas nrog lwm cov haujlwm molecular thiab cov txheej txheem ntawm tes, xws li nuclear mRNA export thiab mRNA lwj, proliferation, sib txawv, autophagy, thiab apoptosis. Qhov kev txaus siab loj hlob hauv elF5A cuam tshuam nrog nws txoj kev koom tes nrog cov kab mob ntawm ntau yam kab mob, suav nrog mob qog noj ntshav, kab mob kis, thiab ntshav qab zib. Nws kuj tau raug pom zoo los ua ib qho kev tiv thaiv kev laus: nws cov qib kev lwj hauv cov hlwb laus, qhov nce qib ntawm cov nquag nquag elF5A ua rau lub cev tsis muaj zog thiab cov hlab ntsha thiab txhim kho lub hlwb. Cov ntaub ntawv tsis ntev los no tau txuas lub luag haujlwm ntawm eIF5A hauv qee qhov pathologies nrog nws txoj haujlwm hauv kev tswj hwm kev noj qab haus huv mitochondria. Lub eukaryotic txhais lus pib qhov tseem ceeb 5A yog upregulated nyob rau hauv ua pa metabolism thiab nws tsis muaj peev xwm txo cov pa oxygen noj, ATP ntau lawm, thiab cov theem ntawm ob peb mitochondrial metabolic enzymes, raws li zoo raws li hloov mitochondria dynamics. Txawm li cas los xij, txawm tias tag nrho cov ntaub ntawv khaws tseg tau txuas nrog eIF5A rau mitochondrial muaj nuj nqi, lub luag haujlwm ntawm molecular thiab cov txheej txheem cuam tshuam tseem tsis tau paub. Hauv kev tshuaj xyuas no, peb tham txog qhov kev tshawb pom txuas eIF5A thiab mitochondria, kwv yees txog nws lub luag haujlwm hauv kev tswj hwm mitochondrial homeostasis, thiab qhia txog nws lub peev xwm ua lub hom phiaj ntawm cov kab mob cuam tshuam nrog lub zog metabolism.

Ntsiab lus:elF5A; mitochondria; txhais; spermidine; mitochondrial ua pa; OXPHOS; TCA

Thov nias ntawm no kom paub ntxiv

1. Molecular Function ntawm eIF5A

Txawm hais tias nrhiav tau yuav luag 50 xyoo dhau los, eukaryotic translation pib qhov tseem ceeb 5A (eF5A) tseem enigmatic nyob rau hauv ntau yam. eIF5A yog ib qho me me, ubiquitous, thiab tseem ceeb cov protein uas tau txais txiaj ntsig zoo thoob plaws eukaryotes thiab archaea [1]. Nws kuj tseem muaj ntau heev - nws yog ntawm 100 cov protein ntau tshaj plaws hauv Saccharomyces cerevisiae, nrog kwv yees li 273, 000 daim ntawv ib lub xov tooj, uas yuav luag ob npaug ntawm cov ribosomes [2]. Keeb kwm tau muab cais ua qhov pib txhais lus 3,4], tom qab ntawd tau tshaj tawm tias lub luag haujlwm tseem ceeb ntawm elF5A yog los txhawb kev txhais lus elongation ntawm mRNAs ntawm cov kab ke encoding rau peptide motifs tshwj xeeb thiab pab txiav tawm los ntawm kev txhawb nqa cov hydrolysis ntawm peptidyl-tRNA. [5-11].

Hauv feem ntau eukaryotes, eIF5A nta ob isoforms, TIF5A thiab TIF51B hauv cov poov xab, thiab EIF5A1 thiab EIF5A2 hauv tib neeg, uas qhia cov amino acid ib ntus tus kheej ntawm ntau dua 90 feem pua ​​​​hauv txhua lub cev thiab qhia nyob rau hauv cov xwm txheej sib txawv. Ntawm no, peb xa mus rau feem ntau tshaj tawm isoforms, Tif51A hauv cov poov xab thiab EIF5A1 hauv tib neeg, xws li elF5A. Nws tsuas yog paub cellular protein uas muaj qhov txawv txav thiab tseem ceeb amino acid hypusine (Ne-({13}}amino-2-hydroxybutyl)lysine). Hypusination yog ib qho tseem ceeb rau eF5A muaj nuj nqi thiab tshwm sim los ntawm ob kauj ruam tom qab kev txhais lus cov tshuaj tiv thaiv uas yuav tsum tau muaj ob lub enzymes, deoxyhypusine synthase (DHPS) thiab deoxyhypusine hydroxylase (DOHH) (Daim duab 1). Ua ntej, DHIPS hloov cov aminobutyl moiety los ntawm polyamine spermidine mus rau e-amino pawg ntawm ib qho tshwj xeeb lysine residue (Lys51 hauv poov xab thiab Lys50 hauv tib neeg) los tsim ib qho nruab nrab. Thib ob, DOHH tam sim ntawd thiab irreversibly catalyzes hydroxylation ntawm deoxyhypusine residue rau hypusine, yielding lub active hvpusinated thiab paub tab daim ntawv ntawm elF5A [12].cistanchYog li ntawd, intracellular hyphenated elF5A (hyp-elF5A) cuam tshuam nrog cellular elF5A kev ua haujlwm. Eukaryotic txhais lus pib qhov tseem ceeb 5A tuaj yeem dhau mus rau lwm qhov kev hloov pauv tom qab, xws li acetylation (hauv Lys47 thiab Lys68 residues), uas yog xav tias tsis suav nrog hyphenation [13,14], lossis phosphorylation (hauv Ser2) [15l, lub luag haujlwm ntawm uas yog tsis to taub kiag li.

Daim duab 1. Polyamine-hypusine pathway thiab nws cov pharmacological inhibitors. Spermidine substrate rau elF5A hyphenation yog tau los ntawm kev hloov pauv ntawm polyamine ornithine hauv putrescine los ntawm enzyme ornithine decarboxylase (ODC); Tom ntej no, spermidine yog synthesized los ntawm putrescine los ntawm spermidine synthase (SPDS). Xwb, spermidine hloov mus ua spermine los ntawm spermine synthase (SPMS). Kev hloov kho Hypusine ntawm lysine-50(tib neeg) lossis lysine-51 (poov tshuaj) residue ntawm elF5A tshwm sim los ntawm kev sib ntxiv ntawm spermidine ntawm ob qhov sib txuas ntawm cov tshuaj tiv thaiv enzymatic.cistanche AustraliaUa ntej, deoxyhypusine synthase (DHPS) hloov cov aminobutyl pawg ntawm spermidine mus rau cov amino pawg ntawm lysine tsim ib qho nruab nrab substrate, uas tsis sib sau. Thib ob, deoxyhypusine hydroxylase (DOHH) ntxiv ib pab pawg hydroxyl thiab tsim cov hypusine residue ntawm eF5A, uas muab cov haujlwm rau cov protein. elF5A tom qab kev hloov pauv hloov pauv tuaj yeem cuam tshuam los ntawm inhibitors ntawm DHPS thiab DOHH, tab sis kuj los ntawm inhibition ntawm ODC, tus nqi txwv enzyme rau spermidine biosynthesis. Daim duab ua tau ua tiav siv BioRender software.

Cistanche tuaj yeem tiv thaiv kev laus

Hais txog cov qauv ntawm elF5A, cov kev tshawb fawb sib txawv, uas nws cov ntsiab lus ntawm archaea mus rau tib neeg, tau luam tawm nyob rau hauv lub xyoo caum dhau los [16-18] qhia li cas hyp-elF5A folds mus rau hauv ib tug ob-domain qauv ntawm feem ntau -sheet cim, nyob rau hauv uas N-terminal feem harbors lub cim feature ntawm eIF5A, hypusine residue [19]. Qhov seem no nyob rau ntawm qhov kawg ntawm qhov txuas ntxiv, tsis muaj teeb meem, thiab nthuav tawm lub voj (hypusine voj) zoo li tRNA. Tom qab khi rau qhov twb-tsim 80S ribosomal complex, hyp-elF5A yog kwv yees nyob ib sab ntawm P-site tRNA overlapping E-site [20-22]. Nyob rau hauv txoj kev no, hyp-elF5A tiv thaiv ribosomes los ntawm stalling ntawm ib ntus los ntawm qhov projecting hypusine-muaj npe mus rau P-site kom sterically txwv txoj hauj lwm ntawm cov residue tso rau nws. Tshwj xeeb, hyp-elF5A txhawb kev sib txuas ntawm cov proteins los ntawm kev nyiam peptide daim ntawv cog lus ntawm qhov tseem ceeb amino acid residues paub tias tsis zoo substrates rau cov tshuaj tiv thaiv, xws li stretches ntawm peb los yog ntau tshaj sib law liag proline residues (PPP) los yog polyproline motifs, tab sis kuj ua ke ntawm proline, glycine, thiab them cov amino acids [9-11]. Yog li, hyp-elF5A pab hauv kev txhais lus tsuas yog ib feem ntawm tag nrho cov neeg mRNA, uas yog nws qhov tshwj xeeb. Hauv kev sib txuas nrog nws lub luag haujlwm tseem ceeb hauv kev txhais lus, hyp-elF5A kuj tseem tuaj yeem ua rau thaj chaw endoplasmic reticulum (ER), qhov uas nws cuam tshuam nrog ribosomes khi rau ER membrane, thiab nws zoo li pab txhawb kev sib koom ua ke ntawm qee cov proteins rau hauv. lub ER, xws li collagen [23-26].cov txiaj ntsig cistancheYog li, thaiv elF5A hyphenation upregulates cov kev ntxhov siab-induced chaperones nyob rau hauv poov xab [25] thiab ua rau ER kev nyuaj siab nyob rau hauv mammalian hlwb [26,27]. Ntau qhov kev tshawb fawb tau qhia tias elF5A koom nrog hauv cov txheej txheem uas tsis ncaj qha cuam tshuam rau cov protein synthesis. Cov yam ntxwv ntawm elF5A qhia tias nws muaj peev xwm cuam tshuam nrog nucleic acids. C-terminal domain zoo li tus mob khaub thuas-shock domain (CSD), muaj nyob rau hauv DNA- thiab RNA-binding proteins, thaum lub N-terminal nqa cov hypusine residue, uas muaj ob tug zoo nqi thiab zoo li spermidine, ib tug molecule paub los cuam tshuam tshwj xeeb. nrog DNA thiab RNA. Tseeb tiag, hyp-elF5A tau raug tshaj tawm los khi rau qee qhov RNA molecules nyob rau hauv ib ntus tshwj xeeb [28,29], thiab pab thauj cov mRNAs tshiab los ntawm cov nucleus mus rau cytoplasm [28,30]. Ntxiv mus, eF5A mutants ua rau muaj kev cuam tshuam loj heev ntawm qhov sib npaug ntawm mRNA kev nrhiav neeg ua haujlwm rau ribosomes rau kev txhais lus thiab nws cov degradation [24,31,32], qhia tias elF5A ua haujlwm hauv cov kauj ruam ntawm mRNA decay downstream ntawm decapping [24,31]. Archaeal IF5A kuj tseem ua lub luag haujlwm hauv RNA metabolism raws li lub teeb ci protein uas koom nrog cov ribosomes tab sis kuj ua haujlwm RNAse [33].

Raws li tau hais dhau los, hyp-elF5A pab txhais cov proteins tshwj xeeb uas muaj cov ntsiab lus tseem ceeb hauv lawv cov amino acid sequences, txawm hais tias nws zoo li tam sim no peb paub tsuas yog ib feem me me ntawm nws lub hom phiaj ncaj qha. Yog li, lub luag haujlwm tseem ceeb uas elF5A ua si hauv cov txheej txheem ntawm tes sib txawv feem ntau yog vim qhov dav ntawm cov haujlwm ntawm tes uas nws lub hom phiaj ncaj qha tam sim no. Ib lub luag haujlwm tseem ceeb ntawm hyp-elF5A nyob hauv cell proliferation thiab tsiaj loj hlob. Eukaryotic txhais lus pib qhov tseem ceeb 5A thiab nws cov hyphenation yog qhov tseem ceeb rau kev loj hlob ntawm tes hauv eukaryotes, thiab kev cuam tshuam ntawm eIF5A lossis DHPS cov noob, nrog rau cov inhibitors ntawm DHPS, ua rau kev loj hlob raug ntes thiab muaj zog tiv thaiv kev loj hlob, suav nrog apoptosis [13, {{ 9}}] ib. Hyp-eF5A kuj kho kom zoo autophagy los ntawm kev txhais lus ntawm autophagy master transcription factor TFEB thiab ATG3protein, tom kawg koom nrog hauv lipidation ntawm LC3B thiab tsim ntawm autophagosome [42,43]. Tsis tas li ntawd, elF5A ua lub luag haujlwm tseem ceeb hauv lub koom haum cytoskeleton kom zoo thiab cov duab ntawm tes [44-46] los ntawm kev txhais cov formins hauv eukaryotes. Hauv cov poov xab, elF5A xav tau rau kev txhais lus ntawm polyproline-muaj formin Bnil, uas koom nrog kev loj hlob ntawm polarized thaum mating [47]. Raws li, ib qho kev sib txuas ntawm cov tshuab tau pom ntawm elF5A thiab diaphanous, cov ntaub ntawv koom nrog hauv kev sib sau ua ke ntawm cov khoom siv hluav taws xob thaum lub sij hawm embryonic dorsal kaw ntawm Drosophila, thiab kev tsiv teb tsaws ntawm neural qia hlwb [48]. Hyp-elF5A kuj tau piav qhia los txhawb kev tsiv teb tsaws ntawm tes, ntxeem tau, thiab metastasis los ntawm kev tswj cov kev qhia ntawm cov teeb meem tseem ceeb xws li RhoA thiab Rho-txuas nrog kinase, ob cytoskeleton-regulatory proteins koom nrog txhawb kev tsiv teb tsaws ntawm tes [49], thiab los ntawm kev tswj ncaj qha MYC biosynthesis ntawm qee qhov kev ncua sijhawm [50]. Tshwj xeeb, EIF5A2 isoform tau pom los txhawb kev hloov pauv ntawm epithelial-mesenchymal hauv ntau hom mob qog noj ntshav [5]. Eukaryotic txhais lus pib qhov tseem ceeb 5A kuj tau cuam tshuam rau hauv kev tswj hwm ntawm apoptosis tab sis cov txheej txheem cuam tshuam zoo li tangled vim tias txoj haujlwm no zoo li cuam tshuam rau kev txhawb nqa kev loj hlob [52-54]. Tsis ntev los no tau pom tias, hauv kev teb rau kev ntxhov siab, hyp-elF5A txhawb kev txhais cov qog nqaij hlav thiab pro-apoptotic factor p53, uas muaj cov polyproline motifs rhiab rau qhov kev txiav txim ntawm elF5A [55] thiab ua haujlwm raws li qhov tseem ceeb ntawm kev saib xyuas. ua rau muaj ntau yam kev pab cuam antiproliferative.

Lub luag haujlwm tseem ceeb eF5A ua si hauv cov txheej txheem cellular tau hais txog cov protein no hauv cov kab mob ntawm ntau yam kab mob tib neeg. Cov pov thawj ntxiv qhia tias hyp-elF5A ua lub luag haujlwm tseem ceeb hauv kev hloov kho tus kab mob propagation. Nws tau raug txhais tias yog ib qho tseem ceeb cofactor ntawm human immunodeficiency virus type 1 (HIV-1) Rev transport factor. Los ntawm tshwj xeeb Rev khi, nws koom nrog hauv kev hloov pauv ntawm cov kab mob tsis sib haum xeeb mRNAs thoob plaws lub hnab ntawv nuclear [56] thiab tuaj yeem coj tus cwj pwm zoo li nucleocytoplasmic shuttling protein [57]. Txawm hais tias HIV yog thawj tus kab mob uas xav kom xav tau elF5A, qhov tseem ceeb no kuj koom nrog kev rov ua dua ntawm lwm cov kab mob, xws li tus kab mob Marburg (MARV) thiab Ebola virus [58]. Qhov thib ob tib neeg pathogenesis nrog ib tug zoo-txhais txuas mus rau elF5A yog ntshav qab zib. Hauv cov qauv nas ntawm ntshav qab zib, hyp-elF5A hauv pancreatic islet -cells yog lub luag haujlwm rau kev txhais lus ntawm cytokine-induced transcripts, nrog rau kev ua kom thiab loj hlob ntawm T pab hlwb [41,59,60]. Ob lub noob caj noob ces encoding elfF5A, EIF5A, thiab EIF5A2, tau qhia nyob rau hauv cov xwm txheej sib txawv. EIF5A1 tau nthuav tawm thoob plaws hauv txhua cov ntaub so ntswg thiab cov cell, thaum EIF5A2 qhia kev txwv tsis pub muaj kev noj qab haus huv cov ntaub so ntswg (yuav luag tsis tuaj yeem kuaj pom) tab sis muaj ntau dhau ntawm qee cov ntaub so ntswg lossis cov qog nqaij hlav cancer. Lub overexpression ntawm ob qho tib si elF5A isoforms tau pom nyob rau hauv ob peb cov qog thiab ua rau cell migration, ntxeem tau, thiab mob cancer metastasis (saib xyuas [51] kom paub meej), tab sis EIF5A2 yog suav hais tias yog ib tug muaj peev xwm oncogene thiab kuaj mob los yog prognostic marker [61,62] vim hais tias Nws cuam tshuam nrog kev ciaj sia tsis zoo, theem kab mob siab, cov lus teb tsis zoo rau cov tshuaj chemotherapeutic, thiab metastasis. Genetic variants ntawm elF5Agenes tau raug txheeb xyuas raws li lub hauv paus ntawm qee yam tsis tshua muaj neurodevelopmental mob hauv tib neeg [63].

Qhov inhibition ntawm elF5A muaj nuj nqi tau tshwm sim los ua lub hom phiaj rau kev kho cov kab mob uas tau hais tseg. Qhov inhibition ntawm eIF5A hyphenation tuaj yeem ua tiav los ntawm DHPS inhibitors, xws li GC7(N1-guanyl-1,7-}diamonheptane), deoxyspergualin, lossis semapimod; DOHH inhibitors, xws li ciclopirox, deferiprone, lossis mimosine; los yog inhibitors ntawm ornithine decarboxylase (ODC), xws li DFMO (difluoro methyl ornithine) (Daim duab 1). DFMO yog ib qho irreversible inhibitor ntawm ODC, uas yog tus nqi-txheej enzyme ntawm polyamine biosynthesis. Yog li, DFMO ua los txo cov qib polyamine thiab tsis tshwj xeeb inhibit eIF5A hyphenation [64]. DFMO tau siv los txo qhov kev rov ua dua ntawm ntau tus kab mob RNA, suav nrog Ebola, dengue, Zika, polio, thiab Coxsackievirus [58,65] thiab hauv kev tiv thaiv / kho mob qog noj ntshav [66]. Deferiprone thiab nws cov qauv analogue, ciclopirox, yog siv nyob rau hauv kev kho mob ntawm hlau overload thiab fungal kab mob, feem. Txawm li cas los xij, tag nrho peb DOHIH inhibitors cuam tshuam rau kev ua haujlwm ntawm lwm cov enzymes, xws li proline hydroxylase enzyme [37]. Ntawm cov paub DHPSinhibitors, GC7, ib qho diaminoheptane derivative, yog qhov ua tau zoo tshaj plaws inhibitor (K; tus nqi rau GC7, 0.01 uM, piv rau Km rau spermidine, 4.5 uM) [67] thiab tau dav siv niaj hnub no rau inhibit elF5A depurination nyob rau hauv mammalian hlwb [68,69]. Tam sim no tsis muaj cov inhibitors uas ua ncaj qha rau elF5A lossis, xaiv ntau dua, ntawm elF5A2: qhov no yog txoj hauv kev rau kev tshawb fawb thiab kev loj hlob yav tom ntej.

Thaum kawg, lub luag haujlwm ntawm elF5A hauv kev laus tau raug tshawb fawb ntau nyob rau xyoo kaum xyoo dhau los.elF5A cuam tshuam rau kev nco mus ntev, hloov lub cev tiv thaiv kab mob, kev ua haujlwm ntawm lub plawv, thiab kev ua haujlwm mitochondrial; kev ua tsis tiav ntawm cov txheej txheem no yog cov cim ntawm kev laus [70]. Hauv kev tshuaj xyuas no, peb tsom mus rau kev sib raug zoo ntawm eF5A thiab mitochondrial metabolism, nrog rau cov kab mob ntsig txog mitochondria, nrog rau lub hom phiaj los muab cov ntsiab lus ntawm cov ntaub ntawv tsis ntev los no txuas elF5A rau mitochondria hauv cov kab mob sib txawv.

2. Mitochondrial Metabolism hauv Kev Noj Qab Haus Huv thiab Kab Mob

Mitochondria yog cov tsim tawm lub zog tseem ceeb hauv daim ntawv ntawm ATP, uas yuav tsum muaj rau cov txheej txheem tseem ceeb ntawm tes. Yog li ntawd, lawv yog qhov tseem ceeb rau lub neej eukaryotic. Mitochondria yog muab los ntawm endosymbiosis ntawm o-proteobacteria thiab tuav ntau txoj hauv kev metabolic, xws li tricarboxylic acid (TCA) cycle, -oxidation, thiab lipid synthesis.txo cov roj cholesterolLub voj voog TCA thiab cov saw hlau thauj hluav taws xob (ETC) tsim ATP los ntawm redox gradient [71]. Cov bilayer subcellular organelles muaj nyob rau hauv lawv tus kheej genome (mtDNA)8 los yog 13 protein-coding genes (nyob rau hauv loj thiab tib neeg, raws li) uas encode tseem ceeb proteins feem ntau cuam tshuam nyob rau hauv oxidative phosphorylation (OXPHOS) [72]. Cov genome no yog replicated thiab transcribed ntawm nws tus kheej ntawm lub nuclear genome, tab sis ob qho tib si genomes yuav tsum ua hauj lwm ua ke los xyuas kom meej lub cell muaj nuj nqi. Nyob ib ncig ntawm 1500 nuclear-encoded proteins yog tsom mus rau mitochondria, uas yuav tsum muaj kev ntshuam, kev ua, thiab kev sib dhos [73]. Los ntawm kev ua cov pa oxygen los muab lub zog rau kev ua haujlwm ntawm tes, mitochondria tau dhau los ua qhov tseem ceeb hauv lub neej aerobic thiab tseem ceeb hauv ntau yam ntawm kev noj qab haus huv, kab mob, thiab kev laus [74-76]. Thaum cov hluav taws xob khiav tawm raws li cov khoom ntawm oxidative respiration thiab ib feem txo qis oxygen, mitochondria tsim cov pa oxygen reactive (ROS). Qhov no tshwm sim txawm tias nyob rau hauv ib txwm muaj kev txo qis oxygen [77,78]. Nyob rau hauv cov kab mob, mitochondria ua haujlwm tsis zoo thiab feem ntau pom peb qhov kev puas tsuaj loj: ntau tshaj ROS emission, uncoupled OXPHOS, thiab txawv txav Ca2 uptake [79,80]. Cov teeb meem no ua rau muaj kev puas tsuaj rau macromolecules thiab kev hloov pauv hauv cov khoom siv hluav taws xob, ib puag ncig redox, mitochondrial signaling, thiab cell viability. Txhawm rau txo cov teebmeem tsis zoo no, mitochondria tau tsim ntau txoj hauv kev tswj kom zoo los tswj lawv cov haujlwm tseem ceeb thiab txo cov kev ntxhov siab mitochondrial. Ib txoj hauv kev tswj kom zoo yog mitophagy, qhov tshwj xeeb autophagic tshem tawm ntawm mitochondria [81].cistanche deserticola phivTsis tas li ntawd, mitochondria qhia qhov muaj zog heev los ntawm cov txheej txheem fusion thiab fission, uas tso cai rau lawv hloov mus rau cov kev ntxhov siab sib txawv los ntawm kev hloov kho mitochondrial tes hauj lwm [82,83]. Lwm qhov tseem ceeb ntawm txoj kev tswj hwm kev ua tau zoo yog cov lus teb rau kev ntxhov siab los ntawm kev cuam tshuam los ntawm cov khoom lag luam thiab kev hloov pauv ntawm cov lipid metabolism, uas muaj qhov cuam tshuam ntawm cov ntsiab lus ntawm cov lus teb rau kev poob siab thiab kev txhais lus attenuation [84]. Tsis tas li ntawd, mitochondria tuaj yeem hnov ​​​​txog matrix protein misfolding thiab ua rau muaj kev hloov pauv hloov pauv los ua kom muaj kev saib xyuas ntawm mitochondrial proteostasis [85]. Thaum qhov kev puas tsuaj ntawm tes loj dhau lawm, mitochondria ua lub luag haujlwm tseem ceeb hauv kev taw qhia apoptotic cell tuag [86].

Mitochondrial kev ua haujlwm poob qis thaum lub hlwb laus [87-89], tab sis kuj nyob rau hauv cov leeg laus, lub plawv, siab, thiab cov ntaub so ntswg adipose [90]. Yog li, nyob rau hauv cov laus hlwb, muaj ib tug txo nyob rau hauv tus naj npawb thiab ceev ntawm mitochondria, raws li zoo raws li nyob rau hauv mitochondrial biogenesis [91] ntau lawm thiab ua pa saw muaj peev xwm / kev ua [92,93]. Cov hnub nyoog laus kuj qhia txog kev hloov pauv mitochondrial dynamics, poob ntawm mitophagy thiab mitochondrial zoo tswj systems, thiab nce mtDNA puas [83,94]. Muab nws lub luag haujlwm tseem ceeb hauv cov hlwb, mitochondrial dysfunction tuaj yeem cuam tshuam rau ntau yam kev lom neeg thiab tau tshwm sim los ua ib qho tseem ceeb ntawm cov kab mob metabolic, hlab plawv, inflammatory, thiab neurodegenerative kab mob; mob qog noj ntshav; thiab ntau yam kab mob uas muaj hnub nyoog [95-99]. Vim li no, nws yog ib qho tseem ceeb kom nkag siab txog cov txheej txheem ntawm mitochondrial biology kom tso cai rau kev txhim kho cov kev kho mob zoo.

3. Kev nthuav qhia ntawm elF5A Isoforms teb txawv rau Cellular Metabolic State

Feem ntau cov eukaryotes muaj ob lub noob caj noob ces encoding ob homologous isoforms ntawm elF5A. Ob lub noob no qhia txog qhov sib txawv ntawm cov qauv hauv cov tsiaj nyeg thiab cov poov xab, qhia txog kev ua haujlwm tshwj xeeb sib txawv, uas, txawm li cas los xij, tseem tsis tau sau meej meej hauv cov ntsiab lus molecular. Cov ntaub ntawv tam sim no feem ntau hais txog kev sib txawv ntawm elF5A isoforms tau txais los ntawm cov kev tshawb fawb hauv cov poov xab thiab qhia txog kev cuam tshuam ntawm cellular metabolic thiab ua pa xeev.

Kev hloov pauv ntawm cov cellular metabolism rau cov xwm txheej sab nraud yog qhov tseem ceeb rau feem ntau cov kab mob, thiab tshwj xeeb tshaj yog rau cov poov xab, uas cuam tshuam nrog kev hloov pauv tsis tu ncua. Qhov kev nthuav qhia ntawm elF5A isoforms qhia tau hais tias tus qauv ntawm kev sib hloov kev cai nyob rau hauv fermentative thiab ua pa mob. Cov kab mob poov xab nyiam mus rau fermentative es tsis ua pa metabolism. Txawm hais tias muaj zog tsawg dua li kev ua pa, hais txog kev tsim ATP, fermentation tso cai rau cov dej num ntawm tes ua haujlwm ntawm tus nqi siab dua thiab ua rau muaj kev sib tw ntau dua thiab muaj sia nyob. Qhov kev nyiam fermentative metabolism no kuj pom muaj nyob rau hauv cov qog nqaij hlav cancer mis, uas qhov kev nce hauv biomass yog qhov tseem ceeb [100].

Glycolysis thiab fermentation poov xab genes yog induced nyob rau hauv lub xub ntiag ntawm oxygen thiab qabzib, whereas cov noob koom nyob rau hauv kev siv ntawm lwm cov pa roj carbon qhov chaw, xws li ua pa enzymes los ntawm lub voj voog TCA, ETC, thiab OXPHOS, yog raug rau cov piam thaj repression [{{0} }]. Cov qib qabzib siab tswj hwm cov haujlwm ntawm cov protein kinase A thiab lub hom phiaj rapamycin complex 1 (TORC1) qhia txoj hauv kev, txhawb kev loj hlob thaum inhibiting mitochondrial ua pa. Nyob rau hauv cov xwm txheej no, TIF51A tau tsim tawm thaum TIF51B qhia tsis zoo, yuav luag tsis pom. Zoo li lwm cov proteins koom nrog hauv kev txhais lus [104-106], Tif51A yog cov nquag nquag thiab tswj tau zoo los ntawm TORC1 rau ob peb txoj haujlwm biosynthetic rau cov khoom noj uas muaj ntau [107]. Tom qab cov piam thaj txo qis thiab muaj cov pa oxygen txaus, cov poov xab hloov pauv lawv cov metabolism hauv kev ua pa aerobic. Thaum lub sijhawm hloov pauv no, qhov kev qhia ntawm TIF51A tau nce ob mus rau plaub npaug [107, ib yam li ntawm cov noob koom nrog hauv TCA lub voj voog, ETC, thiab OXPHOS [101-103,108,109], thaum TIF51B qhia tsis tu ncua. Raws li cov piam thaj hauv cov ntshav poob qis, TORC1 tsis ua haujlwm, ua rau qeeb qeeb ntawm kev txhais lus thiab kev sib txuas ntawm ribosomal Cheebtsam [104-106]. Qhov no txhais tau hais tias kev loj hlob ntawm tes qeeb thiab tsawg dua cytoplasmic txhais lus yog xav tau, tab sis, xav tsis thoob, ntau elF5A protein yog xav tau [107]. Yog li ntawd, raws li kev loj hlob ntawm exponential nyob rau hauv tsis-fermentative tej yam kev mob, xws li glycerol los yog ethanol, TIF51A mRNA qib kuj tau nce ntau dua piv rau cov qib thaum lub sij hawm exponential kev loj hlob ntawm cov piam thaj, whereas TIF51B qib yog downregulated [107]. Cov ntsiab lus tseem ceeb ntawm cov poov xab metabolic reprogramming ntawm ob lub xeev kev noj qab haus huv, fermentation, thiab ua pa, yog protein kinase A, Snf1, thiab heme / oxygen responsive transcription factor Hap1 thiab Hap2/3/4/5 com-plex. Hauv kev hloov pauv, Hap1 thiab Hap4 raug ntxias thiab txhawb nqa cov noob koom nrog hauv cov txheej txheem ua pa, xws li TCA lub voj voog, ETC, thiab OXPHOS [101,110-113]. Hap1 tseem yog qhov tseem ceeb ntawm kev hloov pauv kev koom tes hauv kev txhawb nqa ntawm TIF51A kev qhia tom qab kev hloov pauv ntawm cov metabolism hauv kev ua pa; txoj cai no ploj hauv hap1 mutant [107]. Hap1 teb rau qhov nce hauv heme cellular theem tshwm sim los ntawm augmented metabolic flux rau hauv TCA lub voj voog uas tsim nyob rau hauv cov mob ua pa [108,109,111,114]. Remarkably, cov kev cai caj ces ntawm elF5A yog kom meej meej sib txawv ntawm lwm yam kev txhais lus. Kev qhia ntawm feem ntau cov ntsiab lus txhais tau txo qis tom qab qhov kev hloov pauv hauv metabolic no, tab sis Tif51A qhia tau hais tias muaj kev cai tshwj xeeb thiab ob txoj cai nrog kev pib txo qis los ntawm TORC1 inactivation thiab kev nce zuj zus ntxiv los ntawm kev ua ntawm Hap1 [107)]. Qhov no qhia meej txog lub luag haujlwm tseem ceeb ntawm elF5A hauv cov txheej txheem ua pa.

Los ntawm qhov sib txawv, qib siab oxygen / heme ua rau TIF51B kev nruj kev tsiv los ntawm kev sib koom ua ke ntawm ob DNA-binding repressor proteins Rox1 thiab Mot3 [115-118], nrog Rox1 qhib los ntawm heme-bound Hap1 [110]. Txawm li cas los xij, nyob rau hauv cov xwm txheej hypoxic thiab txo qis heme thiab hlau, Tif51A protein qhia poob. Cov txheej txheem ntawm cov kev cai tsis zoo no tau pom tias yog kev sib xyaw ua ke ntawm kev txo qis hauv kev ua haujlwm ntawm DOHH, uas siv cov pa oxygen ua lub substrate hauv eF5A hydroxylation [119], thiab qhov kev txiav txim ntawm Hap1, uas tuaj yeem ua raws li kev tawm tsam [107] . Ntawm qhov tod tes, Hall ua raws li tus neeg tawm tsam nyob rau hauv cov xwm txheej hypoxic downregulates ROX1, uas induces TIF51B qhia [120].

Hauv cov poov xab, kev tswj hwm ntawm ob qho tib si elF5A isoforms los ntawm Hall los ntawm kev ua kom / tawm tsam ntawm TIF51A kev qhia thiab Roxy-mediated repression / activation ntawm TIF51B tso cai rau cov kev cai ntawm ob lub noob los ntawm ib qho kev hloov pauv. Yog li, qhov kev qhia txawv no cuam tshuam rau cov txiaj ntsig metabolic sib txawv, nrog Tif51A txhawb kev ua pa thiab Tif51B txhawb nqa anaerobic glycolysis. Nws yuav tsum tau muab sau tseg tias cov poov xab Hap1 protein nta tsis muaj homologs nyob rau hauv mammalian hlwb, tab sis lub hav zoov ntawm lwm yam uas tsis yog-homologous transcription factor mediating ib tug zoo xws li cov kev cai ntawm EIF5Al thiab EIF5A2 tib neeg isoforms tsis tuaj yeem txiav tawm. Qhov tseeb, muaj cov piv txwv ntawm cov kab lus sib txawv ntawm eIF5A tib neeg isoforms txuas nrog cov txiaj ntsig metabolic sib txawv. Nyob rau hauv tib neeg hepatocellular carcinoma (ACC) cov qauv kuaj, feem ntau qhia reprogramming ntawm intracellular metabolism.EIE5A2 tau upregulated. Ntxiv mus, ectopic qhia ntawm EIF5A2 nyob rau hauv hHCC hlwb tau nce kev qhia ntawm glycolysis enzymes ua ke nrog lactate dehydrogenase, txhawb anaerobic glycolysis [121]. Yog li ntawd, kev noj qab haus huv thiab lactate secretion tau nce los ntawm kev tswj hwm ntawm glycolytic enzymes, uas yog cov txheej txheem metabolic feem ntau ntawm cov qog nqaij hlav cancer [122].

Tsis tas li ntawd, elF5A tau raug txheeb xyuas tias yog qhov tseem ceeb rau kev qhia ntawm mammalian hypoxia-inducible factor 1 (HIF-1a), tus thawj tswj hwm kev hloov pauv ntawm cov cellular adaptive teb rau hypoxia [119]. Eukaryotic txhais lus pib qhov tseem ceeb 5A hauv nws daim ntawv acetylated, uas tsis ua haujlwm, nce nyob rau hauv lub sijhawm ntev hypoxic thiab yog lub luag haujlwm rau qhov txo qis hauv HIF-1 kev ua haujlwm. Txawm hais tias cov txheej txheem hauv qab eIF5A thiab HIF-1 kev qhia tseem tsis tau piav qhia, cov kev cai no ua rau elF5A lub hom phiaj kho kom zoo nkauj vim HF-1 kho kom haum rau cov lus teb hloov pauv hauv thaj chaw hypoxic ntawm qog spheroids [119,123].

Hauv cov ntsiab lus, cov ntaub ntawv los ntawm cov poov xab thiab tib neeg txhawb nqa qhov sib txawv ntawm EIF5A1 thiab EIF5A2 cov noob txuas rau lub xeev metabolic ntawm cov hlwb, txawm hais tias nws tsis paub meej tias qhov kev qhia txawv no yog qhov ua rau lossis qhov tshwm sim ntawm cov txheej txheem metabolic. Peb xav kom ntxhov siab tias ntau cov kev tshawb fawb tshawb xyuas elF5A muaj nuj nqi hauv cov qauv tsiaj txhu siv cov hypusine inhibitor GC7, uas, txog niaj hnub no, ntseeg tias yuav txo tau cov hyphenation ntawm ob qho tib si elF5A isoforms. Yog tias txhua qhov elF5A isoform txhawb nqa ntau hom metabolism, uas yog, aerobic lossis anaerobic glycolysis, qhov tshwm sim inhibiting hyphenation ntawm ob isoforms ib txhij yog qhov nyuaj dua los txhais.

Kab lus no yog muab rho tawm los ntawm Int. J. Mol. Sci. 2022, 23, 1284. https://doi.org/10.3390/ijms23031284 https://www.mdpi.com/journal/ijms