Umsebenzi ophakamileyo we-Nrf2 kuMsebenzi weMitochondrial

Izidakamizwa ziveliswa ngendlela elawulwayo ukuze zilawulwe iinkqubo ezibalulekileyo emzimbeni womntu, kubandakanywa ukwahlukana kweeseli, ukuvuvukala, ukusebenza komzimba, ukuzenzekelayo, kunye nokunyamezela ukuphendula. Nangona kunjalo, ukuveliswa okungalawulwayo kwezi baxhasi kungenza inxaxheba uxinzelelo oluxhamlayo, ezinokuchaphazela umsebenzi weselula, ezikhokelela ekuphuhlisweni kwesetyhi, izifo ezingapheliyo nomhlaza. Iindlela zomzimba zokhuselo ezikhuselekileyo zilawulwa ngoluhlu lweendlela ezibalulekileyo ezilawula indlela esabela ngayo iseli kumacidizi. I-nyukliya ye-erythroid ehlobene ne-2, into eyaziwa ngokuba yi-Nrf2, isilawuli esiphumelelayo sokumelana kwamaseli kuma-oxidants. Injongo yendiqendu engezantsi kukuxoxa nokubonisa indima ephumayo yeNrf2 kwimisebenzi ye-mitochondrial.

Abstract

I-transcription factor NF-E2 p45-related factor 2 (Nrf2; igama lofuzo i-NFE2L2) ivumela ukulungelelaniswa kunye nokusinda phantsi kweemeko zoxinzelelo ngokulawula ukubonakaliswa kwejenethi ehlukeneyo ye-cytoprotective proteins, kubandakanywa ne-antioxidant, i-anti-inflammatory, kunye ne-detoxification enzymes ngokunjalo. njengeeprotheyini ezincedisa ekulungiseni okanye ekususeni ii-macromolecules ezonakalisiweyo. I-Nrf2 inendima ebalulekileyo ekugcinweni kwe-redox homeostasis yeselula ngokulawula i-biosynthesis, ukusetyenziswa, kunye nokuhlaziywa kwe-glutathione, i-thioredoxin, kunye ne-NADPH kunye nokulawula ukuveliswa kweentlobo ze-oksijini esebenzayo nge-mitochondria kunye ne-NADPH oxidase. Ngaphantsi kweemeko ze-homeostatic, i-Nrf2 ichaphazela i-membrane ye-mitochondrial, i-fatty acid oxidation, ukufumaneka kwe-substrates (i-NADH kunye ne-FADH2 / i-succinate) yokuphefumula, kunye ne-ATP synthesis. Ngaphantsi kweemeko zoxinzelelo okanye ukukhula kwezinto ezikhuthazayo, ukusebenza kwe-Nrf2 kuchasene nokunyuka kwemveliso ye-oksijini esebenzayo kwi-mitochondria ngokusebenzisa i-transcriptional upregulation ye-protein ye-3 kunye nefuthe le-mitochondrial biogenesis ngokugcina amanqanaba e-nuclear factor 1 kunye ne-peroxisome proliferator-activated receptor? i-coactivator 1?, kunye nokukhuthaza i-purine nucleotide biosynthesis. I-Pharmacological Nrf2 activators, ezifana ne-isothiocyanate sulforaphane eyenzeka ngokwemvelo, inqanda ukuvulwa kwe-oxidant-mediated ye-mitochondrial permeability transition pore kunye nokuvuvukala kwe-mitochondrial. Kuyathakazelisa ukuba i-synthetic 1,4-diphenyl-1,2,3-triazole compound, eyenzelwe ekuqaleni njenge-activator ye-Nrf2, yafunyanwa ukukhuthaza i-mitophagy, ngaloo ndlela igalelo kwi-homeostasis ye-mitochondrial jikelele. Ngaloo ndlela, i-Nrf2 ngumdlali obalaseleyo ekuxhaseni ukunyaniseka kwesakhiwo kunye nokusebenza kwe-mitochondria, kwaye le nxaxheba ibaluleke kakhulu phantsi kweemeko zoxinzelelo.

Internet: Bioenergetics, Cytoprotection, Keap1, iMitochondria, i-Nrf2, i-Radicals yamahhala

Iimbalasane

• I-Nrf2 inendima ebalulekileyo ekulondolozeni i-homeostasis yeselula ye-redox.
• I-Nrf2 ithinta i-memitane ye-mitochondrial kunye ne-ATP synthesis.
• I-Nrf2 ichaphazela i-acidified acid acid oxidation.
• I-Nrf2 isekela ingqibelelo yesakhiwo kunye nemisebenzi ye-mitochondria.
• Ama-activator ye-Nrf2 aneempembelelo ezilungileyo xa umsebenzi we-mitochondrial uphathwe.

intshayelelo

I-transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) ilawula ukubonakaliswa kothungelwano lwee-proteins ze-encoding ye-genes kunye nemisebenzi eyahlukeneyo ye-cytoprotective. I-Nrf2 ngokwayo ilawulwa ngokuyinhloko kwinqanaba lokuzinza kweprotheni. Ngaphantsi kweemeko ze-basal, i-Nrf2 yiprotheni ehlala ixesha elifutshane ephantsi kwe-ubiquitination eqhubekayo kunye nokuthotywa kweproteasomal. Kukho iinkqubo ezintathu ezaziwayo ze-ubiquitin ligase ezinegalelo ekuthotyweni kwe-Nrf2. Ngokomlando, umlawuli wokuqala ongalunganga we-Nrf2 oza kufunyanwa yi-Kelch-efana ne-ECH-ehambelana neprotheyini ye-1 (Keap1) [1], iprotheni ye-adapter ye-substrate ye-Cullin 3 (Cul3) / Rbx1 ubiquitin ligase [2], [3], [ 4]. I-Keap1 isebenzisa indlela esebenza kakhulu yomjikelo ukujolisa kwi-Nrf2 yendawo yonke kunye nokuthotywa kweproteasomal, apho i-Keap1 iqhubeka ihlaziywa, ivumela umjikelo ukuba uqhubeke (Umfanekiso 1A) [5]. I-Nrf2 nayo iphantsi kokunciphisa i-glycogen synthase kinase (GSK) 3 /?-TrCP-exhomekeke kwi-Cul1-based ubiquitin ligase [6], [7]. Ngoku kutshanje, kwaxelwa ukuba, ngexesha leemeko zoxinzelelo lwe-endoplasmic reticulum, i-Nrf2 ifumaneka kuyo yonke indawo kwaye ihlaziywe kwinkqubo exutywe yi-E3 ubiquitin ligase Hrd1 [8].

Ukongezelela ekusebenzeni njengeprothini ye-ubiquitin ligase substrate ipilitini, uKap1 nayo inzwa yoluhlu olubanzi lwe-activator-molecule ye-Nrf2 (ebizwa ngokuba yi-inducers) [9]. Ukucima umjikelezo we-Keap1-ulwaphulo oludibeneyo lwe-Nrf2 ngokuchitshiyelwa kwemichiza ye-cysteine ​​ethile kwi Keap1 [10], [11] okanye ngokuphazamisa ngqo iKeap1: I-Nrf2 isixhobo sokubopha [12], [13]. Ngenxa yoko, i-Nrf2 ayinakuhlaziywa, kwaye i-factual faction iqokelela kwaye idlulisela kwi-nucleus (i-Fig. 1B), apho yenza i-heterodimer eneprotein encinci; ibophezela kumacandelo e-antioxidant-response, kwimimandla elawulayo ephezulu yamagalethi ayo ekujoliswe kuyo; kwaye iqalise ukubhalwa kwephepha [14], [15], [16]. Iibhetri yeenjongo ze-Nrf2 ziquka iiprotheyini ezinemisebenzi eyahlukeneyo ye-cytoprotective, kuquka i-enzyme ye-xenobiotic metabolism, iiprotheni ezinemisebenzi yamanxuwa kunye ne-anti-inflammatory, kunye nama-subtit ase-proteasomal, kunye nama-proteins alawula i-homeostasis yamaselula kunye nokuthatha inxaxheba kwimetabolism.

Nrf2: uMlawuli oyiNtloko weeLellu Redox Homeostasis

Umsebenzi we-Nrf2 njengomlawuli oyintloko we-cellular redox homeostasis yamkelwa ngokubanzi. I-gene expression of both catalytic and regulatory subunits of ?-glutamyl cysteine ​​ligase, i-enzyme eyenza inyathelo lokunciphisa izinga kwi-biosynthesis yokunciphisa i-glutathione (GSH), ilawulwa ngokuthe ngqo yi-Nrf2 [17]. I-subunit ye-xCT yenkqubo ye-xc-, engenisa i-cystine kwiiseli, ikwayi-transcriptional target ngqo ye-Nrf2 [18]. Kwiseli, i-cystine iguqulelwa kwi-cysteine, isandulela se-biosynthesis ye-GSH. Ukongeza kwindima yayo kwi-GSH biosynthesis, i-Nrf2 ibonelela ngeendlela zokugcina i-glutathione kwindawo yayo encitshisiweyo ngummiselo olungelelanisiweyo wokubhalwa kwe-glutathione reductase 1 [19], [20], eyanciphisa i-glutathione ene-oxidized ukuya kwi-GSH isebenzisa ukulinganiswa kokunciphisa ukusuka kwi-NADPH. . I-NADPH efunekayo inikezelwa yizinqununu ezine ze-NADPH-generating enzymes, i-malic enzyme 1 (ME1), i-isocitrate dehydrogenase 1 (IDH1), i-glucose-6-phosphate dehydrogenase (G6PD), kunye ne-6-phosphogluconate dehydrogenase (PGD), zonke ezo ngokubhaliweyo kulawulwa ngokuyinxalenye ye-Nrf2 (umzobo 2) [21], [22], [23], [24]. Okumangalisayo kukuba, i-Nrf2 iphinda ilawule i-inducible gene expression ye-cytosolic, i-microsomal, kunye ne-mitochondrial ye-aldehyde dehydrogenase [25], esebenzisa i-NAD (P) + njenge-cofactor, eyenza i-NAD (P) H. Enyanisweni, amanqanaba e-NADPH kunye nomlinganiselo we-NADPH / NADP + aphantsi kwi-embryonic fibroblasts ehlukanisiwe kwiigundane ze-Nrf2-knockout (Nrf2-KO) xa kuthelekiswa neeseli ezivela kuhlobo lwazo lwasendle (WT), kwaye amanqanaba e-NADPH ayancipha kwi-Nrf2 knockdown in. imigca yeseli yomhlaza ene-Nrf2 esebenzayo [26]. Njengoko kulindelwe, amanqanaba e-GSH aphantsi kwiiseli apho i-Nrf2 iphazamisekile; ngokuchaseneyo, ukusebenza kwe-Nrf2 ngeendlela zofuzo okanye i-pharmacological kukhokelela ekulawuleni i-GSH [27], [28], [29]. Okubalulekileyo, i-Nrf2 iphinda ilawule i-gene expression of thioredoxin [30], [31], [32], i-thioredoxin reductase 1 [28], [29], [32], [33], kunye ne-sulfiredoxin [34], eziyimfuneko. ukwenzela ukunciphisa i-thiols yeprotheyini ene-oxidized.

Ngenxa yenxaxheba ebalulekileyo ye-Nrf2 njengomlawuli we-cellular redox homeostasis, akumangalisi ukuba, xa kuthelekiswa neeseli ze-WT, amanqanaba ezityalo ze-oksijeni ezisebenzayo (ROS) ziphezulu kwiiseli apho iNrf2 iphazamisekile (iNrf2-KO) [35]. Lo mahluko ngokukhethekileyo uhlasela umngeni kunye nama-agent abangela uxinzelelo lwe-oxidative. Ngaphezu koko, iiseli ezingenayo kwi-Nrf2 zininzi ngakumbi kwi-toxicity ye-oxidants of different types kwaye azikwazi ukukhuselwa yi-Nrf2 inducers, apho, phantsi kweemeko ezifanayo, kunika ukukhuseleka okuqhubekayo nokuhlala ixesha elide kwii-WT cells [29], [36] , [37]. Ukongeza kwi-homeostasis ye-redox homeostasis, i-Nrf2 nayo ibaluleke kakhulu ekugcinweni kwe-homeostasis ye-mitochondrial redox. Ngaloo ndlela, xa kuthelekiswa ne-WT, i-pool ye-mitochondrial ye-NADH iyonke inyuke kakhulu kwi-Keap1-KO kwaye yancipha ngokuphawulekayo kwi-Nrf2-KO amaseli [35].

Ukusebenzisa ukucatshulwa kweseli ephilayo, sisanda kuhlola iirhafu zokuveliswa kweROS kwimigangatho ye-glioneuronal cocultures kunye neengcezu zengqondo zecala ezihlukeneyo kwi-WT, Nrf2-KO, okanye i-Keap1-knockdown (Keap1-KD) iigundane [38]. Njengoko kulindeleke, izinga lokuveliswa kweROS likhawuleza kwiiNelf2-KO zeeseli kunye nezicubu ezifaniswa namanye ama-WT. Nangona kunjalo, senze into engalindelekanga yokuba, xa kuthelekiswa neWT, iiseli ze-Keap1-KD nazo zinamazinga aphezulu okuveliswa kweROS, nangona ubukhulu bomehluko phakathi kwe-WT kunye ne-Keap1-KD i-genotypes yayincinci kuneyo phakathi kwe-WT ne-Nrf2-KO . ngoko sihlaziya amanqanaba mRNA of NOX2 kunye NOX4, le subunits zokuphosa le oxidase NADPH ezimbini (Nox) isoforms ukuba sele zikhankanyiwe zokugula ingqondo, bafumana ukuba NOX2 yi landa kakhulu phantsi kweemeko Nrf2 ngxaki, kanti NOX4 ke upregulated xa Nrf2 iyasebenza, kodwa nangona kuncinci. Ukulinganiswa, ubukhulu bokugqithisa kwiiseli kunye nezicubu ezivela kumagundane aguqukayo ziyafana nokunyuka okuhambelana nokuveliswa kweROS [38]. Kuyathakazelisa, kungekhona nje ukuba i-Nrf2 ilawula i-NADPH ye-oxidase, kodwa i-ROS eyenziwa yi-NADPH i-oxidase inokuqalisa i-Nrf2, njengoko kuboniswe kwiiseli ze-epithelial pulmonary and cardiomyocytes [39], [40]. Ngaphezu koko, uphando olutshanje luye lwabonisa ukuba ukusebenza kwe-NADPH-dependence-dependence ye-Nrf2 yindlela yokugcina ekhuselekileyo yokukhusela umonakalo we-mitochondrial kunye nokufa kwesisele entliziyweni ngexesha lokunyanzeliswa kwengcinezelo engapheliyo [41].

Ukongezelela kwinto yokwenza umsebenzi we-NADPH oxidase, ukuphefumula kwe-mitochondrial ngenye imvelaphi engundoqo ye-ROS. Ngokusetyenziswa kweprojektri ye-mitochondria e-MitoSOX, sihlolisise igalelo le-ROS yemvelaphi ye-mitochondrial kwi-ROS jikelele kwimveliso ye-glioneuronal cocultures ukusuka kwi-WT, i-Nrf2-KO, okanye i-Keap1-KD iigundane [38]. Njengoko kulindeleke, iiseli ze-Nrf2-KO zinamanani aphezulu e-ROS mitochondrial production ngaphandle kweWT. Ngokuvumelana neziphumo zoveliso lweROS jikelele, amaxabiso emveliso ye-mitochondrial ROS ku-Keap1-KD yayiphakeme kakhulu xa kuthelekiswa neeseli zeWT. Kubaluleke kakhulu, ukukhusela ubunzima be-rotenone bangela ukwanda okwenkqisayo kwimveliso ye-Rito mitochondrial kwimilo yesibini yeWT neKeap1-KD, kodwa ayizange ibe nempembelelo kwiiseli ze-Nrf2-KO. Ngokuphambene nokunyuka okulindelekileyo kwimveliso ye-Rito mitochondrial kwiiseli ze-WT emva kokungeniswa kwe-pyruvate (ukuphucula ukufumaneka kwe-NADH, ukwandisa umlenze we-mitochondrial, kunye nokugcina ukuphefumla), ukuveliswa kweROS kwanciphise kwi-cell Nrf2-KO. Ngokubakho, ezi ziphumo zibonisa ukuba, ngokungabikho kwe-Nrf2: (i) umsebenzi onzima kakhulu, (ii) umsebenzi ongenakunzima wezinto eziyinkimbinkimbi ngenxa yokunciphisa imida, kunye (iii) nomsebenzi ongenakunzima wezinto ezinzima Ndiyinye yezizathu ezibalulekileyo zokuveliswa kwe-ROS mitochondrial production, mhlawumbi ngenxa yokuguqula i-electron flow from complex II.

I-Nrf2 ithinta i-membrane yeMitochondrial Potential and Respiration

I-membrane ye-mitochondrial enokubakho (??m) luphawu lwendalo yonke lwempilo ye-mitochondrial kunye nemeko ye-metabolic yeseli. Kwiseli esempilweni, i-??m igcinwa litsheyini lokuphefumla lemitochondrial. Okubangela umdla kukuba, i-isotopic ezinzileyo yokubhalwa kwe-isotopic kunye ne-amino acids kwinkcubeko-based based proteomics study kwi-estrogen receptor-negative nontumorigenic human breast epithelial MCF10A cell line ibonise ukuba i-electron mitochondrial icandelo lokuthutha i-NDUFA4 ilawulwa yi-pharmacological activation2 (by) kanti ukulawulwa kofuzo kwe-Nrf2 (nge-Keap1 knockdown) ikhokelela ekuthotyweni kwe-cytochrome c oxidase subunits COX2 kunye ne-COX4I1 [42]. Uphononongo lweproteome yesibindi usebenzisa i-gel electrophoresis ene-dimensional-dimensional kunye ne-matrix-assisted laser desorption / ionization mass spectrometry ifumene ukuba i-Nrf2 ilawula ukubonakaliswa kwe-ATP synthase subunit? [43]. Ukongezelela, iprotheni ye-mitochondrial DJ-1, edlala indima ekugcinweni komsebenzi we-complex I [44], kuye kwabikwa ukuba izinzile i-Nrf2 [45], [46], nangona imiphumo ye-neuroprotective ye-pharmacological or genetic activation. ye-Nrf2 izimeleyo kwi-DJ-1 [47]. Nangona kunjalo, iziphumo zolu qwalaselo lomsebenzi we-mitochondrial ayikaphandwa.

Ngokuvumelana nomsebenzi ophazamisekileyo we-complex I phantsi kweemeko zokusilela kwe-Nrf2, i-basal ??m iphantsi kwi-Nrf2-KO ye-mouse embryonic fibroblasts (MEFs) kunye neeseli ze-glioneuronal eziphambili ezikhuliswe ngokuthelekiswa nabalingani babo be-WT (Fig. 3, inset) [35]. Ngokuchaseneyo, i-basal ??m iphezulu xa i-Nrf2 ilawulwa ngokwemfuza ngokusemthethweni (ngokuwisa okanye ukubethelwa kwe-Keap1). Lo mahluko kwi-??m phakathi kwe-genotypes ibonisa ukuba ukuphefumla kuchatshazelwa ngumsebenzi we-Nrf2. Enyanisweni, ukuvavanywa kokusetyenziswa kwe-oksijeni kwi-basal state kuye kwabonisa ukuba, xa kuthelekiswa ne-WT, ukusetyenziswa kwe-oksijeni kuphantsi kwi-Nrf2-KO kunye ne-Keap1-KO MEFs, nge ~ 50 kunye ne-35%, ngokulandelanayo.

Lo mahluko kwi-??m kunye nokuphefumla phakathi kwe-genotypes ubonakaliswa yisantya sokusetyenziswa kwee-substrates zokuphefumla kwe-mitochondrial. Ukusetyenziswa kwesubstrate zomjikelo we-tricarboxylic acid (TCA) (malate/pyruvate, ethi inyuse imveliso ye-complex I substrate NADH) okanye i-methyl succinate, i-substrate ye-complex II, ibangela ukunyuka kwe-stepwise kwi-??m kuzo zombini i-WT kunye ne-Keap1-KD neurons, kodwa izinga lokunyuka liphezulu kwiiseli ze-Keap1-KD. Okubaluleke ngakumbi, iimilo zokuphendula kwezi substrates zomjikelezo we-TCA zahlukile phakathi kwee-genotypes ezimbini, apho ukunyuka okukhawulezileyo kwi-??m kwiiseli ze-Keap1-KD phezu kokudibanisa kwe-substrate kulandelwa kukuhla ngokukhawuleza kunokuba i-plateau, iphakamisa ngokungaqhelekanga. ukusetyenziswa kwe-substrate ngokukhawuleza. Ezi ziphumo zihambelana ngokusondeleyo kunye namanqanaba asezantsi kakhulu (ngo-50�70%) we-malate, i-pyruvate, kunye ne-succinate eye yabonwa emva kwe-1-h pulse ye- [U-13C6] glucose kwi-Keap1-KO xa kuthelekiswa ne-WT MEF. iiseli [24]. Kwi-Nrf2-KO neurons, yi-pyruvate kuphela ekwazi ukunyusa i-??m, kanti i-malate kunye ne-methyl succinate ibangela ukuchithwa okuncinci. Impembelelo ye-Nrf2 kwimveliso ye-mitochondrial substrate ibonakala iyona ndlela iphambili apho i-Nrf2 ichaphazela umsebenzi we-mitochondrial. Isalathiso se-mitochondrial NADH redox index (ibhalansi phakathi kokusetyenziswa kwe-NADH nge-complex I kunye nokuveliswa kwe-NADPH kumjikelo we-TCA) iphantsi kakhulu kwiiseli ze-Nrf2-KO xa kuthelekiswa nabalingane babo be-WT, kwaye ngaphezu koko, amaxabiso okuhlaziywa kwamachibi echibi. I-NADH kunye ne-FADH2 emva kokuvinjelwa kwe-IV eyinkimbinkimbi (ngokusetyenziswa kwe-NaCN) iyancipha kwiiseli eziguqukayo.

Kwi-mitochondria eyodwa kwingqondo ye-murine kunye nesibindi, ukuxhaswa kwee-substrates ze-complex I okanye kwi-complex II kwandisa izinga lokusetyenziswa kwe-oksijini ngakumbi xa i-Nrf2 ivuliwe kwaye ingasebenzi kakuhle xa i-Nrf2 iphazamiseka [35]. Ngaloo ndlela, i-malate ibangela izinga eliphezulu lokusetyenziswa kwe-oksijini kwi-Keap1-KD xa kuthelekiswa ne-WT, kodwa umphumo wayo ubuthathaka kwi-Nrf2-KO mitochondria. Ngokufanayo, phambi kwe-rotenone (xa i-complex ivaliwe), i-succinate yenza ukusetyenziswa kwe-oksijini kusebenze kakhulu kwi-Keap1-KD xa kuthelekiswa ne-WT, ngelixa impendulo kwi-Nrf2-KO mitochondria iyancipha. Ukongezelela, i-Nrf2-KO iinkcubeko eziphambili ze-neuronal kunye neegundane zivakalelwa ngakumbi kwi-toxicity ye-II inhibitors i-3-nitropropionic acid kunye ne-malonate, kanti i-intrastriatal transplantation ye-Nrf2-overexpressing astrocytes ikhusela [48], [49]. Ngokufanayo, iigundane ze-Nrf2-KO zivakalelwa ngakumbi, ngelixa i-genetic okanye i-pharmacological activation ye-Nrf2 ineziphumo zokukhusela, i-neurotoxicity ebangelwa yi-complex I-inhibitor 1-methyl-4-phenylpyridinium ion kwi-1-methyl-4-phenyl-1,2,3,6, I-49-tetrahydropyridine imodeli yezilwanyana ze-Parkinson? [50], [51], [52], [53].

Umlinganiselo wokulawula ukuphefumula (RCR), umlinganiselo we-State 3 (i-ADP-ivuselelwe) kwi-State 4 yokuphefumula (akukho ADP ekhoyo), iyancipha ngokungabikho kwe-Nrf2, kodwa i-RCR ifana phakathi kwe-Keap1-KD kunye ne-WT mitochondria [35] ]. Njengoko i-RCR ibonakalisa iqondo lokudityaniswa komsebenzi wekhonkco lokuphefumla le-mitochondrial kwi-phosphorylation ene-oxidative, oku kufunyaniswayo kubonisa ukuba izinga eliphezulu lokuphefumla kwi-Keap1-KD mitochondria alikho ngenxa yokudibanisa i-phosphorylation ene-oxidative. Iphinda iphakamise ukuba i-phosphorylation ye-oxidative isebenze ngakumbi xa i-Nrf2 ivuliwe. Izinga eliphezulu lokuphefumla kwi-Keap1-KD mitochondria iyahambelana namanqanaba aphezulu emveliso ye-ROS ye-mitochondrial njengoko amazinga aphezulu okuphefumla anokukhokelela ekwandeni kokuvuza kwe-electron. Nangona kunjalo, phantsi kweemeko zokuxinzezeleka kwe-oxidative, ukuveliswa kwe-ROS okwandisiweyo kuchasene ne-Nrf38-exhomekeke kwi-transcriptional upregulation ye-protein ye-2 (UCP3), eyandisa i-proton conductance ye-membrane yangaphakathi ye-mitochondrial kwaye ngenxa yoko iyancipha ukuveliswa kwe-superoxide [3]. Ngoku kutshanje, kuboniswe ukuba imveliso ye-lipid peroxidation i-62-hydroxy-4-nonenal idibanisa i-Nrf2 exhomekeke kwi-UCP2 kwi-cardiomyocytes; oku kunokubaluleka ngokukodwa ekukhuseleni phantsi kweemeko zoxinzelelo lwe-oxidative ezifana nezo ngexesha le-ischemia-reperfusion [3].

I-Nrf2 ichaphazela ukuphumelela kwe-Phosphorylation ye-Oxyidative kunye ne-Synthesis ye-ATP

Ngokuvumelana nefuthe le-Nrf2 ekuphefumleni, kwingqondo kunye nesibindi se-mitochondria, ukusilela kwe-Nrf2 kubangela ukunciphisa ukusebenza kakuhle kwe-phosphorylation ye-oxidative (njengoko kuqikelelwa ngumlinganiselo we-ADP kwi-oksijeni, esetyenziselwa i-ATP synthesis), kanti i-Nrf2 isebenze (Keap1) -KD) inesiphumo esichasayo [35]. Xa kuthelekiswa ne-WT, amanqanaba e-ATP aphezulu kakhulu kwiiseli kunye ne-constitutive upregulation ye-Nrf2 kwaye iphantsi xa i-Nrf2 ichithwa phantsi [64] okanye iphazamisekile [35]. Ngaphezu koko, ukusetyenziswa kwe-inhibitors ye-oxidative phosphorylation (oligomycin) okanye i-glycolysis (iodoacetic acid) ibonise ukuba i-Nrf2 iguqula indlela iiseli ezivelisa ngayo i-ATP. Ke, kwi-WT neurons, i-oligomycin ibangela ukuhla okupheleleyo kwe-ATP kunye ne-iodoacetic acid ayinayo enye isiphumo. Ngokuphawulekayo, kwiiseli ze-Nrf2-KO, i-oligomycin yandisa amanqanaba e-ATP, athi ke acothe, kodwa ngokupheleleyo, aphelelwe yi-iodoacetic acid, ebonisa ukuba ukungabikho kwe-Nrf2, i-glycolysis, kunye ne-phosphorylation ye-oxidative, iyona mthombo oyintloko wemveliso ye-ATP. Kuyathakazelisa ukuba, nangona ukwanda kokusebenza kakuhle kwe-phosphorylation ye-oxidative kwiiseli ze-Keap1-KD, ukongezwa kwe-oligomycin kubangela ukuhla kwe-~80% kumanqanaba e-ATP, kunye ne-iodoacetic acid ibangela ukuhla kwe-~20%. Ngaloo ndlela, ukusilela kwe-Nrf2 okanye ukusetyenziswa kwayo kunciphisa igalelo le-phosphorylation ye-oxidative kwaye yandisa igalelo le-glycolysis malunga nokuhlanganiswa kwe-ATP. Esi siphumo sivakaliswa ngokukodwa xa i-Nrf2 ingekho kwaye ihambelana nokuxhomekeka kwe-??m kubukho be-glucose phakathi [35] kunye namanqanaba okwanda kwe-glycolytic intermediates (G-6-P, F-6-P). , i-dihydroxyacetone phosphate, i-pyruvate, kunye ne-lactate) emva kokubethelwa kwe-Nrf2 [24].

Ukunyuka kwamanqanaba e-ATP emva kokuvinjelwa kwe-F1F0-ATPase nge-oligomycin ibonisa ukuba ukungabikho kwe-Nrf2, i-F1F0-ATPase isebenza njenge-ATPase kwaye kungekhona i-synthase ye-ATP, oko kukuthi, isebenza ngasemva. Olu tshintsho luhle kakhulu lubonisa imfuneko yokumpompa iiprotons ngapha kwenwebu ye-mitochondrial engaphakathi kwinzame zokugcina i-??m, eyona nto ibalulekileyo kwimfezeko yokusebenza kwale organelle. Ukuguqulwa komsebenzi we-F1F0-ATPase kubonakaliswe yi-depolarization ye-mitochondrial eqatshelweyo ekulawuleni i-oligomycin kwiiseli ze-Nrf2-KO, ezihluke kakhulu kwi-hyperpolarization eyenzekayo kwi-WT okanye i-Keap1-engenayo i-35]. Ngokubanzi, kubonakala ngathi phantsi kweemeko ze-Nrf2 ukusilela kwe-ATP iveliswa ngokuyinhloko kwi-glycolysis, kwaye le ATP isetyenziswe ngokuyinxalenye yi-F1F0-ATPase ukugcina i-??m.

I-Nrf2 Iphucula i-Acidity Acidity Acid Oxidation yeMitochondrial

Isiphumo sokusilela kwe-Nrf2 kwi-??m sichazwa ngokukodwa xa iiseli zifakwe phakathi ngaphandle kwe-glucose, kwaye i-??m i-~50% ephantsi kwi-Nrf2-KO xa kuthelekiswa neeseli ze-WT [35]. Ngaphantsi kweemeko zokunciphisa i-glucose, i-mitochondrial fatty acid oxidation (FAO) ngumboneleli omkhulu we-substrates yokuphefumula kunye ne-phosphorylation ye-oxidative, ebonisa ukuba i-Nrf2 inokuchaphazela i-FAO. Enyanisweni, ukusebenza kakuhle kwe-FAO kuzo zombini i-chain-long-chain (C16: 0) i-fatty acid palmitic acid kunye ne-short-chain (C6: 0) i-hexanoic acid iphezulu kwi-Keap1-KO MEFs kunye nentliziyo eyedwa kunye ne-mitochondria yesibindi kune-mitochondria yabo. Abalingani be-WT, ngelixa iphantsi kwiiseli ze-Nrf2-KO kunye ne-mitochondria [65]. Ezi ziphumo zibaluleke kakhulu ebantwini: ngokwenene, utshintsho lwe-metabolic lubonisa ukuhlanganiswa okungcono kwe-FAO kunye nomsebenzi womjikelezo we-TCA kuye kwabikwa ukuba kwenzeke kwizifundo zongenelelo lwabantu kunye nokutya okutyebileyo kwi-glucoraphanin, i-precursor ye-classical Nrf2 activator sulforaphane [ 66].

Ngexesha lenyathelo lokuqala le-FAO ye-mitochondrial, i-pro-R hydrogen ye-?-carbon ishiya njenge-hydride enciphisa i-FAD cofactor kwi-FADH2, ethi idlulisele ii-electron kwi-ubiquinone (UbQ) kwikhonkco lokuphefumla, ekugqibeleni libe negalelo kwimveliso ye-ATP. . Nangona ukukhuthazwa kwe-FAO ngepalmitoylcarnitine ngokungabikho kweglucose kubangela ukunyuka okulindelweyo kumanqanaba e-ATP kwi-WT kunye neeseli ze-Keap1-KO, kunye nokunyuka kwe-ATP ngokukhawuleza kwiiseli ze-Keap1-KO, unyango olufanayo aluvelisi utshintsho lwe-ATP kwi-Nrf2-KO. MEFs [65]. Olu vavanyo lubonisa ukuba, ngokungabikho kwe-Nrf2, i-FAO icinezelwe, kwaye ngaphezu koko, ibandakanya ukunyanzeliswa kwe-FAO njengenye yezizathu zamanqanaba aphantsi e-ATP phantsi kweemeko ze-Nrf2 [35], [64].

Ngokucacileyo, iifom ze-293 T zabantu apho iNrf2 ikhutshwe ngayo i-CPT1 kunye ne-CPT2 [67], ii-isoform ze-carnitine palmitoyltransferase (CPT), i-enzyme yokunciphisa isantya kwi-FAO ye-mitochondrial. Ngokuvumelana, ama-mRNA amanqanaba e-Cpt1 aphantsi kwi-Nrf2-KO xa kuthelekiswa namagundane e-WT [68]. I-CPT ivuselela ukudluliselwa kweqela le-acyl ye-acyl-CoA e-long-fat chain-coA esuka kwi-coenzyme A ukuya kwi-carnitine kwaye ngoko ivumela ukungenisa kwe-acylcarnitine ukusuka kwi-cytoplasm ukuya kwi-mitochondria. Nangona oku kungakhange kuhlolwe kuze kube yimini, kunokwenzeka ukuba ngaphezu kweempembelelo ze-CPT1, iNrf2 inokuchaphazela nomsebenzi wale nzyme ngokulawula amanqanaba e-allosteric inhibitor yayo eyintloko, i-malonyl-CoA. Oku kungenxa yokuba, ngeendlela ezingabonakali ngokucacileyo, i-Nrf2 ilawula kakubi ukubonakaliswa kwe-coaroyl CoA desaturase (SCD) [69] kunye ne-citrate lyase (CL) [69], [70]. Okumangalisayo kukuba, ukunqonkqoza okanye ukuvinjelwa kwe-SCD kukhokelela ekwandiseni i-phosphorylation kunye nokusebenza kwe-protein kinase (AMPK) esebenzayo ye-AMP [71], [72], [73], kwaye kunokucingelwa ukuba, ngokungabikho kwe-Nrf2, amanqanaba eSDD iya kunyuka, ngokunciphisa umsebenzi we-AMPK. Oku kungaphakanyiswa ngakumbi ngamanqanaba eeprotheyini ancitshisiweyo e-AMPK aye afunyaniswa kwiimbambiso ze-Nrf2-KO amagundane [68], ukufumanisa okukufutshane kwesivumelwano kunye namazinga e-AMPK awandisiweyo, achazwe kwi-Liap1-KD amagundane [74]. Esinye isiphumo somsebenzi we-AMPK owehlayo ukukhutshwa kwe-phosphorylation ye-inhibitory (kwi-Ser79) ye-acetyl-CoA carboxylase (i-ACC) [75], enokubakho ngokubanzi ngokubhalwa komthetho ngokungabikho kwe-Nrf2 kuba ilawulwa yi-Nrf2 isebenze [70 ]. Umsebenzi ophezulu we-ACC, ngokubambisana nenkcazo ye-CL ephakanyisiweyo eyokwandisa umveliso we-acetyl-CoA, umgca we-ACC, unokugcina ukwandiswa kwamanqanaba emveliso ye-ACC, malonyl-CoA. Amanqanaba aphakamileyo ye-malonyl-CoA aya kuvimbela i-CPT, ngaloo ndlela anciphise ukuthuthwa kwe-acid acids kwi-mitochondria. Ekugqibeleni, i-Nrf2 ilawula kakuhle i-CD36 [76], i-translocase ehambisa i-acids acids kwi-plasma nakumamembrane e-mitochondrial. Ngaloo ndlela, enye indlela iNrf2 inokuchaphazela ngayo ukusebenza kwe-FAO yemithachondrial kukulawula ukungenisa kwama-acids e-long chain acids kwi-mitochondria.

Ukongezelela ukuhanjiswa komthetho we-transcription, i-Nrf2 inokuguqula nokusebenza kakuhle kwe-FAO ye-mitochondrial ngeziphumo zayo kwi-cell redox metabolism. Oku kunokwenzeka ngokukhethekileyo xa umsebenzi we-Nrf2 uphantsi okanye ungekho, iimeko ezitshintsha isimo se-redox yeselula kwi-oxidized state. Enyanisweni, ii-enzyme ezininzi ze-FAO ziye zachongwa nje ngokuba zijongene nokutshintsha kwe-redox. Enye ye-enzyme i-acyl-CoA dehydrogenase (i-VLCAD) eninzi kakhulu, eyenza ngaphezu kwe-80% kwimisebenzi ye-palmitoyl-CoA yokuqheliswa komzimba kumathambo omntu [77]. Okuthakazelisayo, u-Hurd et al. [I-78] ibonise ukuba i-VLCAD iqulethe i-cysteine ​​resi resies eguqula kakhulu isimo sayo se-redox xa kuvezwa i-heart rate ye-rod mitochondria kwi-H2O2. Ukongezelela, i-S-nitrosylation yeVLCAD ye-murine hepatic kwiCys238 ithuthukisa ukusebenza kakuhle kwe-enzyme [79], kwaye mhlawumbi i-oxidation ye-cysteine ​​efanayo ingaba nefuthe echaseneyo, ekugqibeleni iyanciphise ukusebenza kwe-FAO yemithachondrial. Ngoko ke kunokwenzeka ukuba, nangona amaqondo e-VLCAD ahlukanga kakhulu kwi-WT, i-Nrf2-KO, okanye i-Keap1-KO MEFs [i-65], umsebenzi we-VLCAD umsebenzi we-enzyme ungaphantsi ekungabikho kwe-Nrf2 ngenxa yamanqanaba aphakamileyo yeROS.

Ngokusekelwe kuzo zonke ezi ziphumo, kunokuphakanyiswa ukuba (umzobo 3): ngokungabikho kwe-Nrf2, amanqanaba e-NADPH aphantsi ngenxa yokunciphisa ukubonakaliswa kwe-ME1, i-IDH1, i-G6PD, kunye ne-PGD. Amanqanaba okunciphisa i-glutathione nawo aphantsi ngenxa yokunciphisa ukubonakaliswa kwe-enzymes ethatha inxaxheba kwi-biosynthesis yayo kunye nokuvuselelwa kunye namanqanaba aphantsi e-NADPH afunekayo ukuguqulwa kwe-oxidized kwifom encitshisiweyo ye-glutathione. Ukubonakaliswa okuphantsi kwe-ME1 kuya kunciphisa ichibi le-pyruvate elingena kwi-mitochondria, kunye ne-glycolysis ibe ngumthombo omkhulu we-pyruvate. Isizukulwana se-NADH sihamba kancinci, sikhokelela ekusebenzeni kakubi kwe-complex I kunye nokwanda kwemveliso ye-ROS ye-mitochondrial. Ukuncitshiswa kwe-FAD ukuya kwi-FADH2 nako kucotha, ubuncinci kwinxenye ngenxa ye-oxidation ye-fatty acid engasebenzi kakuhle, ebeka emngciphekweni ukuhamba kwe-electron ukusuka kwi-FADH2 ukuya kwi-UbQ nakwi-complex III. Njengoko i-UbQH2 i-activator ye-succinate dehydrogenase [80], ukunciphisa ukubunjwa kwayo kunokunciphisa umsebenzi we-enzyme ye-succinate dehydrogenase. Ukunyuka kwamanqanaba e-superoxide kunye ne-hydrogen peroxide kunokuthintela umsebenzi onzima we-II ngakumbi [81]. Ukusebenza okuphantsi kwe-fatty acid oxidation kunegalelo ekunciphiseni ukufumaneka kwe-substrate yokuphefumula kwe-mitochondrial kunye nokuveliswa kwe-ATP kwi-phosphorylation ye-oxidative. Njengendlela yokubuyisela, i-glycolysis iphuculwe. I-ATP synthase isebenza ngomva, njenge-ATPase, kumzamo wokugcina i-??m.

I-Nrf2 kunye ne-Mitochondrial Biogenesis

Kuye kwaxelwa ukuba, xa kuthelekiswa ne-WT, izibindi ze-Nrf2-KO zeegundane zinomxholo ophantsi we-mitochondrial (njengoko kunqunywe ngumlinganiselo we-mitochondrial kwi-nuclear DNA); oku kuncipha ngakumbi nge-24-h ngokukhawuleza kuzo zombini iimpuku ze-WT kunye ne-Nrf2-KO; ngokuchaseneyo, nangona kungekho nto yahlukileyo kwi-WT phantsi kweemeko eziqhelekileyo zokutya, umxholo we-mitochondrial kwiigundane ezinomsebenzi ophezulu we-Nrf2 awuchaphazeli ngokuzila ukudla [82]. Okuthakazelisayo, ukuxhaswa kunye ne-Nrf2 activator (R)-?-lipoic acid [83], [84], [85] ikhuthaza i-mitochondrial biogenesis kwi-3T3-L1 adipocytes [86]. Iiklasi ezimbini zabalawuli benyukliya abakhutshelweyo badlala indima ebalulekileyo kwi-mitochondrial biogenesis. Iklasi yokuqala zizinto ezikhutshelweyo, ezifana ne-nuclear respiratory factor11 kunye ne-2, elawula ukubonakaliswa kwee-genes encoding subunits ze-complex zokuphefumla ezintlanu, i-mitochondrial translational components, kunye ne-heme biosynthetic enzymes ezibekwe kwindawo ye-mitochondrial matrix [88]. Piantadosi et al. [89] ibonise ukuba i-Nrf2 exhomekeke kwi-transcriptional upregulation ye-nuclear factor 1 ikhuthaza i-mitochondrial biogenesis kwaye ikhusela i-cytotoxicity ye-cardiotoxic anthracycline chemotherapeutic agent doxorubicin. Ngokwahlukileyo, uZhang et al. [82] baye baxela ukuba ukusetyenziswa kofuzo lwe-Nrf2 akuchaphazeli i-basal mRNA ibonakaliso ye-nuclear factor 1 kwisibindi se-murine.

Udidi lwesibini lwabalawuli bombhalo wenyukliya abanemisebenzi ebalulekileyo kwi-mitochondrial biogenesis zi-transcriptal coactivators, ezifana ne-peroxisome proliferator-activated receptor? iicoactivators (PGC)1? kunye ne-1?, ehambelana nezinto ezibhaliweyo, i-basal transcriptional kunye noomatshini be-RNA-splicing, kunye ne-histone-modifying enzymes [88], [90], [91]. Inkcazo yosapho lwe-PGC1 yee-coactivators iphenjelelwa ziimpawu ezininzi zokusingqongileyo. Unyango lwe-fibroblasts yabantu kunye ne-Nrf2 activator sulforaphane ibangela ukwanda kwe-mitochondrial mass kunye nokufakwa kwePGC1? kunye nePGC1? [92], nangona ukuxhomekeka okunokwenzeka kwi-Nrf2 akuzange kuhlolwe kolu cwaningo. Nangona kunjalo, iimpuku zesifo seswekile apho i-Nrf2 inokuthi isebenze yi-Keap1 gene hypomorphic knockdown (db/db:Keap1flox/?:Nrf2+/+) okanye iphazamiseke (db/db:Keap1flox/?:Nrf2?/?) ine-hepatic esezantsi ye-PGC1? amanqanaba okuthetha kunezilwanyana zokulawula (db/db:Keap1flox/+:Nrf2+/+) [93]. Akukho mahluko kumanqanaba e-mRNA yePGC1? zibonwa kwizibindi zeempuku ezingezonondiabetic ezinokuba yi-WT okanye i-Nrf2-KO, ngelixa la manqanaba asezantsi kwi-Nrf2-overexpressing (Keap1-KD kunye nezilwanyana ze-Keap1-KO) ezikhethekileyo [82]. Ngokucacileyo, ukukhawuleza kwe-24-h kwandisa amanqanaba ePGC1? I-mRNA kwizibindi zeempuku zazo zonke i-genotypes, kodwa ukunyuka kukhulu kakhulu kwizibindi ze-Nrf2-KO xa kuthelekiswa ne-WT okanye i-Nrf2-overexpressing mice. Xa kuthelekiswa ne-WT, iimpuku ze-Nrf2-KO ezifumana usulelo lwe-septic okanye ukwenzakala okukhulu kwemiphunga ngenxa yosulelo lubonisa ukunyuswa okubhalwe phantsi kwe-nuclear factor 1 kunye ne-PGC1? [94], [95]. Ngokudibeneyo, olu qwalaselo lucebisa ukuba indima ye-Nrf2 ekugcineni amanqanaba okuphefumla kwenyukliya 1 kunye nePGC1? luntsonkothile kwaye lubonakala kakhulu phantsi kweemeko zoxinzelelo.

Ukongeza ekubonakalisweni kofuzo lwe-encoding mitochondrial proteins, i-mitochondrial biogenesis ifuna ukuhlanganiswa kweenucleotides. Ukusetyenziswa kwe-Genetic ye-Nrf2 kuphucula i-purine biosynthesis ngokuphakamisa indlela ye-pentose phosphate kunye ne-metabolism ye-folate kunye ne-glutamine, ngokukodwa kwiiseli ezikhula ngokukhawuleza (umzobo 2) [24]. Uhlalutyo lwe-transcriptome ye-Drosophila eguquguqukayo elahlekileyo ye-mitochondrial serine / threonine protein kinase I-PTEN-induced putative kinase 1 (PINK1) ibonise ukuba ukungasebenzi kwe-mitochondrial kukhokelela ekukhuselweni kokubhalwa kwemfuza echaphazela i-nucleotide metabolism [96], iphakamisa i-nucleotide metabolism [1], iphakamisa i-nucleotide metabolism. imele indlela yokukhusela kwimiphumo ye-neurotoxic yokunqongophala kwe-PINK2. I-Nrf2 ilawula ukubonakaliswa kwe-phosphoribosyl pyrophosphate amidotransferase (PPAT), eyenza ukungena kwi-de novo purine nucleotide biosynthetic pathway, kunye ne-mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) (Fig. 97). Le yokugqibela yi-enzyme ene-bifunctional ene-dehydrogenase kunye ne-cyclohydrolase imisebenzi ebalulekileyo ekuboneleleni zombini i-glycine kunye ne-formate njengemithombo yeeyunithi zekhabhoni enye ye-purine biosynthesis kwiiseli ezikhula ngokukhawuleza [2]. Ke ngoko kusenokwenzeka ukuba ukusebenza kwe-Nrf1 kunokukhusela kwaye kunokubuyisela umva ukungasebenzi kakuhle kwe-mitochondrial kukusilela kwe-PINK2. Enyanisweni, ukusetyenziswa kwe-pharmacological ye-Nrf408 nge-sulforaphane, okanye i-triterpenoid RTA-1, ibuyisela i-??m kwaye ikhusela iiseli ezinqongopheleyo ze-PINK98 kwi-dopamine toxicity [2]. Nangona iindlela ezisisiseko zibonakala zinzima, kunye, ezi ziphumo zibonisa ukuba umsebenzi we-NrfXNUMX unokuchaphazela i-mitochondrial biogenesis ngokuchaphazela amanqanaba okubonakaliswa kwezinto ezibalulekileyo zokubhaliweyo kunye ne-coactivators, kunye nokuphucula i-nucleotide biosynthesis.

I-Nrf2 ne-Mitochondrial Integrity

Nangona ubungqina obuchanekileyo abukho ngaso sonke isikhathi, kukho izibonakaliso ezinamandla ukuba i-Nrf2 ibalulekile ukuthembeka kwe-mitochondrial, ngokukodwa phantsi kweemeko zoxinzelelo lwe-oxidative. I-Mitochondria eyodwa ngaphandle kwengqondo kunye nesibindi seengwenya eziye zalawulwa enye i-dose ye-Nrf2 activator sulforaphane ayimelana nokuvulwa kweporechondrial empowerment pore transition (mPTP) ebangelwa yi-tert-butylhydroperoxide [99], i-100]. I-MPTP, ubunzima obangela ukuba i-membrane yangaphakathi ye-mitochondrial ibe yinto enokubonakalayo kwiimolyuli kunye nezixuku ukuya kwi-1500 Da, isandul 'ukuza kubonakala ukuba yenziwe kwi-dimers ye-F0F1-ATP synthase [101]. Ukuxhatshazwa kwe-sulforaphane ukuxhatshazwa kwe-mPTP ngokuvelisa i-mtochondrial GSH, i-glutathione peroxidase i-1, i-enzyme ye-malic 3, kunye ne-thioredoxin i-2 yonke iyahlukunyezwa kwiinqununu ze-mitochondrial ezixhomekeke kwizilwanyana eziphathekayo (100].

Umonakalo weprotheyini ye-Mitochondrial kunye nokuphazamiseka kokuphefumla okubangelwa yimveliso ye-electrophilic lipid peroxidation i-4-hydroxy-2-nonenal iyancipha kwi-mitochondria eyodwa kwi-cortex ye-cerebral ye-sulforaphane-treated mice [102]. Kwiiseli ze-renal epithelial kunye nakwizintso, i-sulforaphane ikhusela kwi-cisplatin- kunye ne-gentamicin-induced toxicity kunye nokulahlekelwa kwe-??m[103], [104]. Ukukhuselwa kwiphaneli ye-oxidants (i-superoxide, i-hydrogen peroxide, i-peroxynitrite) kunye ne-electrophiles (i-4-hydroxy-2-nonenal kunye ne-acrolein) kunye nokunyuka kwe-mitochondrial yokukhusela i-antioxidant kuye kwabonwa kunyango lwe-rat aortic smooth muscle cells kunye ne-sulforaphane [105]. ]. Kwimodeli yokulimala kwezintso ezichaseneyo, i-preconditioning ye-ischemic ye-ischemic isandul 'ukuboniswa ukuba ineempembelelo ezikhuselayo, kubandakanywa ukuvinjelwa kokuvulwa kwe-mPTP kunye nokuvuvukala kwe-mitochondrial, ngokusebenza kwe-Nrf2 ngenxa yokuvinjelwa kwe-GSK3? [106].

I-Mitophagy, inkqubo apho i-mitochondria engasebenziyo ifakwe ngokukhethiweyo yi-autophagosomes kwaye isiwe kwi-lysosomes ukuze ithotywe kwaye isetyenziswe kwakhona yiseli, ibalulekile kwi-homeostasis ye-mitochondrial [107], [108]. Nangona kungekho budlelwane be-causative phakathi kwe-Nrf2 kunye ne-mitophagy buye basekwa, kukho ubungqina bokuba i-transcription factor inokubaluleka kulawulo lwekhwalithi ye-mitochondrial ngokudlala indima kwi-mitophagy. Oku kunokubonakala ngakumbi phantsi kweemeko zoxinzelelo lwe-oxidative. Ngaloo ndlela, kumzekelo we-sepsis, ukunyuka kwamanqanaba e-autophagosome marker MAP1 i-chain chain 3-II (LC3-II) kunye neprotheyini ye-cargo p62 kwi-24 h postinfection igxininiswe kwi-Nrf2-KO xa kuthelekiswa neegundane ze-WT [109] . I-inducer encinci ye-molecule ye-mitophagy (ebizwa ngokuba yi-p62-mediated mitophagy inducer, i-PMI) isanda kufunyanwa; le ngqungquthela ye-1,4-diphenyl-1,2,3-triazole ekuqaleni yayiyilwe njenge-activator ye-Nrf2 ephazamisa ukusebenzisana kwe-transcription factor kunye ne-Keap1 [110]. Ngokufana neeseli apho i-Nrf2 ilawulwa ngokofuzo (Keap1-KD okanye i-Keap1-KO), iiseli ezivezwe kwi-PMI zinokuphumla okuphezulu ??m. Okubalulekileyo, ukwanda kwendawo ye-mitochondrial LC3 ebonwa emva kokuba unyango lwe-PMI lweeseli ze-WT lungenzeki kwiiseli ze-Nrf2-KO, ezibonisa ukubandakanyeka kwe-Nrf2.

Ekugqibeleni, ukuhlaziywa kwezixhobo zesibindi kuye kwabonisa ukuba khona kwe-mitochondria ekhunyiweyo kunye ne-curiti eyancitshiweyo kwaye yaphazamisa iimbumba kwi-hepatocytes ye-Nrf2-KO, kodwa kungekhona i-WT, iigundane ezazisondla ukutya okunamafutha amaninzi kwiiveki ze-24; ngokugqithiseleyo, ezi zibopheko zibonisa ubungqina obucacileyo bokuxinzezeleka kweengxaki kunye nokuvuvukala [68]. Ingagqitywa ukuba i-Nrf2 inendima ebalulekileyo ekugcineni ingqibelelo ye-mitochondrial phantsi kweemeko zengcinezelo yokuxhamla nokukhupha.

I-Sulforaphane kunye neZiphumo zayo kuMhlaza, ukusweleka, ukuGuga, uBongo kunye nokuziphatha, isifo sentliziyo kunye nokunye

I-Isothiocyanates zizinye zezona zibalulekileyo zityalo zezityalo onokuzifumana kwisondlo sakho. Kule vidiyo ndiyenzela iimeko ezinzulu kunazo zonke eziye zenziwa. Ukufutshane okufutshane? Dlulela kwisihloko ozithandayo ngokuchofoza enye yeengongoma zangezantsi. Umgca wexesha eliphantsi.

Amacandelo aphambili:

• 00: 01: 14 - I-cancer kunye nokufa
• 00: 19: 04 - Ukuguga
• 00: 26: 30 - Ubunono nokuziphatha
• I-00: I-38: 06 - I-recap yokugqibela
• 00: 40: 27 - Dose

Umgca wexesha elipheleleyo

• 00: 00: 34 - Ukuqaliswa kwe-sulforaphane, ingqwalasela ephambili yevidiyo.
• I-00: I-01: 14 - Ukusetyenziswa kwemifuno yeCruciferous kunye nokunciphisa kuzo zonke izizathu zokufa.
• I-00: 02: 12 - Umngcipheko womhlaza we-prostate.
• I-00: 02: 23 - Ingozi yomhlaza wesibeletho.
• I-00: 02: 34 - Umdlavuza womlenze kwingozi yokubhema.
• 00: 02: 48 - Ingozi yomhlaza wesifuba.
• I-00: 03: 13 - I-Hypothetical: kuthekani ukuba unomdlavuza? (ukungenelela)
• I-00: I-03: 35 - Indlela engabonakaliyo yokuqhuba umhlaza kunye nokufa kwedatha yokudibanisa.
• 00: 04: 38 - Sulforfane nomhlaza.
• I-00: 05: 32 - Ubungqina benkomo obonakalisa impembelelo enamandla ye-broccoli inhluma ehluthwayo ekuphuculweni kwe-tumor kwi-rats.
• I-00: I-06: 06 - Impembelelo yokuxhaswa ngokuthe ngqo kwe-sulforaphane kwizigulane zomhlaza wesibeletho.
• I-00: I-07: 09 - Ukuqokelela i-isothiocyanate i-metabolites kwimizimba yesisu.
• I-00: 08: 32 - Ukuvinjelwa kweeseli zomhlaza zesisu.
• 00: 08: 53 - Isifundo somlando: i-brassicas yasungulwa njengezakhiwo zezempilo nakwiRoma lasendulo.
• I-00: 09: 16 - I-Sulforfane ikhono lokuphucula ukwanda kwe-carcinogen (benzene, acrolein).
• I-00: 09: 51 - NRF2 njengenguqu yokuguqula izakhi nge-antioxidant response elements.
• I-00: 10: 10 - Indlela eyenziwa ngayo i-NRF2 isebenzise ukwanda kwe-carcinogen nge-glutathione-S-conjugates.
• I-00: I-10: I-34 - i-Brussels ihluma iyakhuphula i-glutathione-S-transferase kwaye iyanciphisa umonakalo we-DNA.
• I-00: 11: I-20 - i-Broccoli ihluma isiselo iphakamisa ibhenene ngaphandle kwe-61%.
• I-00: I-13: I-31 - I-Broccoli ihluma i-homogenate ikwandisa i-enzymes e-antioxidant ephezulu.
• I-00: I-15: 45 - Ukusetyenziswa kwemifuno yeCruciferous kunye nokufa kwesifo senhliziyo.
• I-00: I-16: I-55 - i-Broccoli ihluma i-powder iphucula i-lipids yegazi kunye nesifo sengqondo senhliziyo yesifo se-2.
• 00: 19: 04 - Ukuqala kwecandelo lokuguga.
• I-00: I-19: I-21 - I-Sulforaphane-ukutya okunomsoco kwandisa ubomi be-beetles ukusuka kwi-15 ukuya ku-30% (kwiimeko ezithile).
• I-00: 20: 34 - Ukubaluleka kokuvuvuka okuphantsi kwexesha elide.
• I-00: I-22: I-05 - Imifuno e-Cruciferous kunye ne-broccoli ihlumela i-powder ibonakala iyanciphisa iindidi ezahlukahlukeneyo zokumangalisa abantu.
• I-00: 23: 40 - Ukuhlaziywa kwe-mid-video: umdlavuza, izigulane eziguga
• I-00: I-24: I-14 - Iziphumo zemouse zibonisa ukuba i-sulfurephane inokuphucula ukusebenza kwe-immune ngexesha lokuguga.
• I-00: I-25: I-18 -Sulforaphane ithuthukise ukunyuka kweenwele kwimodeli ye-mouse yokukhangela. Umfanekiso kwi-00: 26: 10.
• 00: 26: 30 - Ukuqala kwecandelo lobuchopho kunye nokuziphatha.
• I-00: 27: 18 - Impembelelo ye-broccoli ihluma i-autism.
• 00: 27: 48 - Umphumo we-glucoraphanin kwi-schizophrenia.
• I-00: I-28: 17 - Ukuqala kwengxoxo yokudandatheka (iindlela kunye nezifundo).
• I-00: 31: 21 - Uvavanyo lweMouse usebenzisa i-10 imizekelo eyahlukeneyo yokuxinezeleka okubangelwa uxinzelelo kubonisa ukuba i-sulforaphane efana neyofana ne-fluoxetine (prozac).
• I-00: I-32: I-00 - Ukufundiswa kubonisa ukungena ngokuthe ngqo kwe-glucoraphanin kwiimicebe kusebenza ngokufanayo ekukhuseleni ukudandatheka kwindlela yokuxhatshazwa kwentlalo.
• I-00: I-33: 01 - Ukuqala kwecandelo lokuvelisa i-neurodegeneneration.
• 00: 33: 30 - Sulforaphane kunye nesifo se-Alzheimer.
• 00: 33: 44 - Sulforaphane kunye nesifo sikaParkinson.
• 00: 33: 51 - iSulforaphane nesifo sikaHongtington.
• I-00: 34: I-13 - I-Sulforfane iphakamisa ama-proteins.
• 00: 34: 43 - Ukuqala kwecandelo lokulimala kwengqondo elibuhlungu.
• I-00: I-35: I-01 - I-Sulforaphane injected ngokukhawuleza emva kwe-TBI iphucula imemori (isifundo se mouse).
• I-00: 35: 55 - iSulforaphane kunye ne-plastic neuronal.
• I-00: I-36: I-32 - I-Sulforfane iphucula ukufunda kwi-type II yesifo sikashukela kwiimiceba.
• I-00: 37: 19 - iSulforaphane kunye ne-duchenne i-dystrophy muscular.
• I-00: 37: 44 - I-Myostatin inhibition kwiiseli ze-satellite ze-muscle (in vitro).
• I-00: 38: 06 - Ukuhlaziywa kwexesha elide: i-mortality kunye nomhlaza, umonakalo we-DNA, uxinzelelo lwe-oxidative kunye nokuvuvukala, i-benzene excretion, isifo se-cardiovascular, uhlobo lwesi-2 seswekile, iimpembelelo kwingqondo (ukudandatheka, autism, schizophrenia, neurodegeneration), indlela ye-NRF2.
• I-00: I-40: 27 - Iingcamango zokuqikelela umthamo wamahlumela e-broccoli okanye i-sulforfane.
• I-00: I-41: I-01 - i-Anecdotes xa ihluma ekhaya.
• I-00: 43: 14 - Ekuphekeni kwamaqondo okushisa kunye nomsebenzi we-sulforaphane.
• I-00: 43: 45 - Gut bacteria ukuguqulwa kwe-sulforaphane kwi-glucoraphanin.
• I-00: I-44: I-24 - I-Supplements isebenza ngcono xa idibene ne-myrosinase esebenzayo kwimifuno.
• I-00: I-44: I-56 - Amasu okupheka kunye nemifuno e-cruciferous.
• 00: 46: 06 - Isothiocyanates njenge-goitrogens.

I-Nrf2 yinto ebhaliweyo yokubhaliweyo eyenza indima ebalulekileyo kwinkqubo yokukhusela i-antioxidant system yomzimba womntu. Into ephendulayo ye-antioxidant, okanye i-ARE, yindlela yokulawula i-gene. Ucwaningo oluninzi luye lwabonisa ukuba i-Nrf2, okanye i-NF-E2 ehlobene ne-2, ilawula iintlobo ezahlukeneyo zeGEN eziqhutywe kuzo zonke iintlobo zeeseli. I-Nrf2 yafunyanwa ukuba idlale indima ebalulekileyo ekukhuselweni kwamaselula kunye ne-anti-carcinogenicity, ebonisa ukuba i-Nrf2 ingaba unyango osebenzayo ekulawuleni izifo ezingenayo i-neurodeergenerative kunye neentsholongwane ezikholelwa ukuba zibangelwa ukunyanzeliswa kwe-oxidative. UDkt Alex Jimenez DC, i-CCST Insight

Ukuphetha

Nangona imibuzo emininzi ihlala ivulekile, ubungqina obukhoyo bovavanyo bubonisa ngokucacileyo ukuba iNrf2 ngumdlali obalulekileyo ekugcinweni kwe-homeostasis ye-mitochondrial kunye nokuthembeka kwezakhiwo. Le nxaxheba ibaluleke ngokukodwa phantsi kweemeko zengxubevange, i-electrophilic, kunye nokuvutha kwengqondo xa ukukwazi ukulungelelanisa iimpendulo ze-NRf2-mediated-response zichaphazela impilo jikelele kunye nokuphila kweseli kunye nomzimba. Indima ye-Nrf2 kumsebenzi we-mitochondrial ibonisa olunye uhla lweendlela ezibanzi ze-cytoprotective ezichanekileyo ngolu hlobo lombhalo. Uninzi lweemeko zesifo sengqondo zinoxinzelelo lwe-oxidative, ukuvuvukala, kunye ne-mitochondrial dysfunction njengezinto ezibalulekileyo ze-pathogenesis, ukusebenza kwe-pharmological yeNrf2 inesithembiso sokuthintela izifo kunye nokunyangwa. Ukuqonda ngokubanzi iinkqubo ezichanekileyo ezenziwa ngu-Nrf2 umsebenzi we-mitochondrial kubalulekile ekuqulunqweni koqulunqo lwezilingo zekliniki ezizayo kwaye unokunika ama-biomarkers amasha ukubeka ingqwalasela ekusebenzeni ngempumelelo.

Imibulelo

Sciencedirect.com/science/article/pii/S0891584915002129

Injongo yeli nqaku lingasentla ibikukuxoxa�kunye nokubonisa �indima evelayo ye-Nrf2 kumsebenzi wemitochondrial. Nrf2, okanye inyukliya yezinto ezinxulumene nezixhobo ze-2, ngumlawuli ovelayo wokuchasana kwamaselula kwii-oxidants ezinokuthi zibe negalelo kuxinzelelo lwe-oxidative, echaphazela ukusebenza kwamaselula kunye nokukhokelela ekuphuhlisweni kobutyhefu, izifo ezingapheliyo, kunye nomhlaza. Ngelixa imveliso yee-oxidants emzimbeni womntu inokusebenzela iinjongo ezahlukeneyo, �kubandakanya ukwahlulwahlulwa kweeseli, ukudumba, ukusebenza komzimba, i-autophagy, kunye nokuphendula koxinzelelo, kubalulekile ukulawula ukuveliswa kwazo okugqithisileyo ukuthintela imiba yezempilo. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nemiba yempilo yomgogodla. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

U khankanywe kwi: Sciencedirect.com

Ingxoxo yesihloko esongezelelweyo: cBuhlungu obuBuhlungu

Umqolo obuhlunguSesinye sezona zizathu zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Iimpawu ezibuhlungu zangasemva kwisizathu sesibini esiqhelekileyo sokutyelelwa yi-ofisi kagqirha, ngaphezulu kwenani losulelo oluphezulu lokuphefumla. Phantse iipesenti ezingama-80 zabemi baya kufumana iintlungu zangasemva kube kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ngenxa yoku, ukwenzakala kunye / okanye iimeko ezixineneyo, ezinje ngedisni, ekugqibeleni inokukhokelela kwiimpawu zentlungu emva. Ukulimala kwezemidlalo okanye ukulimala kwengozi yemoto kudla ngokuba yimbangela eqhelekileyo yeentlungu zangasemva, nangona kunjalo, ngamanye amaxesha ukunyakaza okulula kunokuba neziphumo ezibuhlungu. Ngethamsanqa, ukhetho olulolunye unyango, olufana nokunyamekela kwe-chiropractic, lunokunceda ukunciphisa intlungu emva kokusetyenziswa kohlengahlengiso lomqolo kunye nokunyanzeliswa kwezandla, ekugqibeleni kuphuculwe intlungu. �

I-EXTRA EXTRA | ISIHLOKO ESIBALULEKILEYO: Kunconywe i-El Paso, TX I-Chiropractor

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