Targeting Lub Mitochondrial Permeability Transition Pore Los Tiv Thaiv Cov Hnub Nyoog Uas Muaj Kev Puas Tsuaj Cell Thiab Neurodegeneration Part 1

Cov txheej txheem kev laus yog txuam nrog kev hloov pauv tseem ceeb hauv kev ua haujlwm mitochondrial. Cov kev hloov pauv no hauv mitochondrial muaj nuj nqi yog xav kom muaj kev tsim cov pa oxygen ntau ntxiv (ROS), uas dhau sijhawm ua rau cov cell tuag, senescence, cov ntaub so ntswg degeneration, thiab kho cov nqaij mos.

Raws li tib neeg lub neej ncua ntxiv, kev laus tau dhau los ua lub ntsiab lus tseem ceeb hauv lub neej niaj hnub. Txawm hais tias feem ntau ntseeg tau tias cov neeg laus muaj kev nco tsis muaj zog, ntau cov kev tshawb fawb tau pom tias tsis muaj qhov tsim nyog txuas ntawm cov txheej txheem kev laus thiab kev nco. Ntau tus neeg laus tseem tuaj yeem khaws cov kev nco zoo heev, thiab qee qhov tuaj yeem ua tau zoo dua cov hluas.

Ua ntej, cov neeg laus tej zaum yuav muaj kev paub thiab kev paub ntau dua li cov hluas. Kev paub thiab kev paub yog qhov tseem ceeb ntawm kev nco, thiab lawv tuaj yeem pab cov neeg laus nco qab cov ntaub ntawv tshiab zoo dua. Tsis tas li ntawd, kev cob qhia kev nco thiab kev txawj ntse rau cov neeg laus tuaj yeem txhim kho lub hlwb ua haujlwm thiab pab lawv tswj kev nco zoo dua.

Qhov thib ob, kev noj qab haus huv ntawm lub cev yog tus yuam sij rau kev tswj kev nco. Kev laus tsis tas txhais hais tias kev noj qab haus huv yuav poob qis. Yog tias cov neeg laus muaj peev xwm tswj hwm kev noj qab haus huv, ua haujlwm tsis tu ncua, thiab tswj kev ua neej kom raug, lawv lub cim xeeb yuav zoo dua li cov tub ntxhais hluas uas twb muaj kev noj qab haus huv.

Tau kawg, kev laus cuam tshuam rau tib neeg lub peev xwm kev txawj ntse. Tab sis qhov no tsuas yog qhov xwm txheej ntuj. Qhov peb yuav tsum tau ua yog tswj tus cwj pwm zoo, lees paub qhov tseeb tias peb loj hlob tuaj, thiab siv zog ua haujlwm kom noj qab haus huv, ua kom nco, thiab tswj peb lub peev xwm thiab lub neej zoo.

Nyob rau hauv luv luv, kev laus tsis tas txhais hais tias ib tug nco poob. Cov neeg laus tuaj yeem tswj hwm lawv lub cim xeeb thiab kev txawj ntse los ntawm ntau txoj hauv kev, thiab txawm tias dhau qee cov tub ntxhais hluas. Peb yuav tsum hwm cov kev paub thiab kev paub ntawm cov neeg laus thiab pab lawv ua lub luag haujlwm zoo hauv lub neej. Nyob rau tib lub sijhawm, peb yuav tsum siv peb lub cim xeeb thiab kev txawj ntse kom ntau li ntau tau thaum peb tseem hluas los tsim lub hauv paus rau peb lub neej yav tom ntej. Nws tuaj yeem pom tias peb yuav tsum txhim kho peb lub cim xeeb, thiab Cistanche tuaj yeem txhim kho peb lub cim xeeb zoo vim tias Cistanche yog cov tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Lub mitochondrial permeability hloov pauv pore (mPTP) zoo li yuav ua lub luag haujlwm tseem ceeb hauv cov txheej txheem no, vim tias ROS nce ntxiv qhib mPTP, uas ntxiv ROS ntau lawm.

Kev raug mob thiab kab mob kuj tseem xav tias yuav ua rau kom mPTP qhib, thiab mob ntev, qis qis yog qhov cim ntawm kev laus.Nicotinamide adenine dinucleotide (NAD+) tuaj yeem cuam tshuam qhov zaus thiab lub sijhawm ntawm mPTP qhib; Txawm li cas los xij, NAD + qib paub tias poob qis nrog lub hnub nyoog, ntxiv dag zog rau mPTP qhib thiab nce ROS tso tawm.

Kev tshawb fawb txog cov kab mob neurodegenerative, tshwj xeeb yog Parkinson's disease (PD) thiab Alzheimer's disease (AD), tau nthuav tawm cov kev tshawb pom tseem ceeb txog mPTP qhib thiab kev laus. Parkinson tus kab mob cuam tshuam nrog kev txo qis hauv mitochondrial complex I kev ua haujlwm thiab nce oxidative puas tsuaj ntawm DNA, ob qho tib si txuas nrog mPTP qhib thiab tom qab ROS tso tawm.

Ib yam li ntawd, AD muaj feem cuam tshuam nrog nce mPTP qhib, raws li pom los ntawm amyloid-beta (A) kev cuam tshuam nrog lub pore regulator cyclophilin D (CypD).

Cov phiaj xwm kev kho mob uas tuaj yeem txo qhov zaus thiab lub sijhawm ntawm mPTP qhib tuaj yeem muaj peev xwm tiv thaiv kev poob qis hauv cell thiab cov ntaub so ntswg ua haujlwm hauv ntau lub nruab nrog rau hauv nruab nrab paj hlwb.

1. Taw qhia

Cov neeg laus coob zuj zus tuaj thoob ntiaj teb. Yog li ntawd, qhov tshwm sim ntawm cov kab mob uas muaj hnub nyoog xws li AD, osteoporosis, sarcopenia, thiab osteoarthritis kuj nce.

Qhov kev nce ntxiv hauv cov hnub nyoog muaj feem cuam tshuam muaj qhov cuam tshuam loj, tsis zoo rau lub neej zoo rau cov neeg mob thiab lawv tsev neeg thiab tseem ua rau muaj lub nra hnyav rau cov kab ke kho mob.

Kev nkag siab zoo ntawm cov cellular thiab molecular mechanisms hauv qab kev laus yog lub hauv paus rau txoj kev loj hlob zoo thiab kev kho mob txhais lus tshiab ntawm kev kho tshiab thiab cov tswv yim tiv thaiv.

Kev ua haujlwm tsis ntev los no tau pom tias kev hloov pauv hauv mPTP muaj nuj nqi tuaj yeem ua rau ncaj qha rau cellulardysfunction nrog kev laus [1–3]. Cov kev hloov no suav nrog nce hauv ROS ntau lawm, induction ntawm cellular senescence (tshwj xeeb tshaj yog nyob rau hauv cov laus qia hlwb), thiab ua kom inflammasome, tom kawg pab ncaj qha mus rau lub xeev ntawm o feem ntau hu ua "inflammaging" [1-3].

mPTP tsis ua haujlwm tau raug suav tias yog ib qho tseem ceeb ntawm cov kab mob neurodegenerative pathologies los ntawm nws lub luag haujlwm hauv kev sib tsoo mitochondrial membrane muaj peev xwm, ua rau mitochondrial ua pa ua haujlwm, tso mitochondrialCa2+ thiab cytochrome c, thiab txhim kho ROS tiam [4-7]. Yog li, mPTP tau txais kev saib xyuas ntxiv raws li lub hom phiaj kho mob.

Kev sib raug zoo ntawm mPTP thiab cov tsim ntawm mitochondrial reactive oxygen hom (mROS) tau cuam tshuam cov kev txaus siab tseem ceeb hauv cov ntsiab lus ntawm kev laus thiab cov ntaub so ntswg degeneration [8].

Tsis ntev los no, nws tau pom tias mROS tuaj yeem txhawb kev qhib mPTP, uas tuaj yeem ua rau ntxiv mROS ntau lawm thiab tso tawm [9]. Qhov kev tawm tswv yim zoo no thaum kawg ua rau muaj ntau dhau ntawm ROS tsub zuj zuj. ROS tsub zuj zuj hauv turndamages nuclear DNA, activates proapoptotic signaling pathways, thiab drives cellular laus [10-12].

Ntawm qhov tod tes, ROS tuaj yeem ua rau qee qhov xwm txheej qhib txoj hauv kev tiv thaiv, txo kev ntxhov siab ntawm mitochondria, thiab ua kom lub neej muaj sia [1, 11]. Tam sim no nws tau xav tias mPTP ua lub luag haujlwm tseem ceeb hauv kev sib koom ua ke ntawm cov teebmeem ntawm mROS thiab yog li no tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev laus [8].

Hauv qhov kev tshuaj xyuas no, peb tham txog ntau yam txheej txheem uas ua rau muaj kev ua kom lawv PTP thiab lub hnub nyoog cuam tshuam ntawm tes raug pom los ntawm kev ua kom mPTP. Tsis tas li ntawd, peb sib tham txog cov kev kho mob uas muaj peev xwm ua rau lub hom phiaj ntawm mPTP thiab tej zaum yuav yog li ntawd inhibit qhov cuam tshuam ntawm kev laus thiab kev raug mob.

1.1. Qauv thiab Tsim ntawm mPTP.

Ntau yam structuralcomponents ntawm mPTP yog implicated nyob rau hauv permeabilitytransition (PT); Txawm li cas los xij, tag nrho cov qauv ntawm mPTPis tseem tsis to taub tag nrho.

Yav dhau los nws tau xav tias qhov pore muaj ntau yam xws li avoltage-dependent ion channel (VDAC), adenine nucleotide transporter (ANT), thiab peripheral benzodiazepinereceptor [13, 14].

Cov ntsiab lus no tau piav qhia los ua lub luag haujlwm tshwj xeeb: VDAC cuam tshuam nrog benzodiazepinereceptor thiab tswj cov kev hloov pauv ntawm cov roj (cholesterol) mus rau qhov chaw nruab nrab, thaum ANT tso cai rau kev nkag mus ntawm phosphorylated thiab nonphosphorylatedderivatives ntawm adenine nucleotides [15].

Tsuas yog rau ANT, uas yog xav tias yuav ua raws li cov cai tswj hwm molecule, cov kev sim caj ces tsis ntev los no tau txiav txim siab cov ntsiab lus hais saum toj no raws li cov khoom ntawm mPTP [16].

Yog li, peb nthuav tawm ntawm no cov qauv tsis ntev los no hais txog mPTP muaj pes tsawg leeg nrog kev nkag siab tias cov no tuaj yeem hloov kho luv luv.Cov qauv tsis ntev los no ntawm pore muaj pes tsawg leeg pom tau tias F1F0}(F)-ATP synthase yog cov khoom tseem ceeb ntawm lub pore thiab qhov kev tswj hwm. molecule CypD yog protein ntau modulator ntawm mPTP [17].

Hauv cov qauv no, mPTP tshwm sim los ntawm kev hloov pauv tshwm sim ntawm F1F0 (F)-ATP synthase tom qab Ca2+ khi, tej zaum los ntawm kev hloov Mg2+ ntawm qhov chaw catalytic [18].

Txawm hais tias daim ntawv dimeric lossis daim ntawv monomeric ntawm F1F0 (F)-ATP synthase yog tsim nyog los nce PT tseem yog qhov kev sib cav loj [19, 20]. Txawm li cas los xij, F1F0 (F)-ATPsynthase cov xwm txheej raws li qhov pore tivthaiv tau txais kev txhawb nqa los ntawm geneticmanipulation ntawm F1F0 (F)-ATP synthase [20, 21], los ntawm kev ntsuas electrophysiological [20, 22–24. ], thiab los ntawm mutagenesis ntawm cov residues ntawm F1F0 (F)-ATP synthase [18, 25–27].

Ntawm qhov tod tes, Walker thiab cov npoj yaig tau tawm tswv yim tias F1F0 (F)-ATP synthase tsis yog ib qho tseem ceeb ntawm cov pore [28, 29]. Lawv qhov kev xav yog raws li kev soj ntsuam uas txawm tias tom qab ablating subunits b thiab OSCP ntawm F1F0(F)-ATP synthase, mitochondrial PT tseem tshwm sim [29].

Matrix o o tau siv los txiav txim siab PT vim hais tias ntev mPTP qhib hauv vitro yog ua raws li cov kua diffusion nrog matrix o [30].Cov lus nug muaj, txawm li cas los xij, tau raug tsa hais txog cov kev tshawb pom no. Bernardi [17] tshwj xeeb tau sau tseg tias qhov tsis muaj qhov rov ua dua thiab calibration nrog cov pore-forming agents zoo li alamethicin tuaj yeem cuam tshuam kev txhais cov ntaub ntawv.

Qhov cuam tshuam rau kev ua pa tom qab F1F0 (F)-ATP synthaseknockout tsa cov lus nug ntxiv. Kev ua pa ua pa tau poob qis mus rau ntawm 10 thiab 20% ntawm cov txiaj ntsig pom nyob rau hauv cov tsiaj qus tom qab F1F0 (F)-ATP synthaseknockout [29]. Lub zog tsav tsheb hauv kev ua pa mitochondriafor Ca2+ tsub zuj zuj yog lub hauv-tsis zoo membranepotential tsim los ntawm kev ua pa [31, 32].

Tsis tas li ntawd, Ca2+ uptake yog them-compensated los ntawm kev nce H + twj tso kua mis los ntawm txoj hlab pa [17]. Yog li, nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias qhov siab tshaj plaws ntawm Ca2+ uptake yog txwv los ntawm qhov siab tshaj plaws ntawm H + siv los ntawm cov kab ua pa [33].

Thaum extramitochondrial Ca2+ qib siab tshaj 2 μM, qhov tom kawg ua tus nqi txwv [34]. Nws et al. [28] siv 10 μM pulsesof Ca2+ los ntxias PT; Yog li ntawd, Ca2+ uptake los ntawm mitochondrialacking subunits c, b, thiab OSCP yuav tsum tau qis dua thiab tsis zoo ib yam rau cov tsiaj qus mitochondria[17]. Qhov no ua rau muaj lus nug txog Ca2+ tuav lub peev xwm, kev ntsuas siv los ntawm Nws li al. [28] los txiav txim mPTPopening.

Nws muaj peev xwm hais tias kev ua pa inhibition vim tsis muaj qee qhov subunits yuav tsis tas mus li lub sijhawm.

Cov txheej txheem muaj peev xwm tuaj yeem tshwm sim uas rov ua dua qhov kev qhia ntawm F1F0 (F)-ATP synthase thiab ua rau lub cev ua pa. Thaum xav txog qhov kev tshawb pom saum toj no, F1F0 (F)-ATPsynthase tsis tuaj yeem txiav txim siab ua ib qho porecomponent.

Qhov kev sim siab tshaj plaws txhawb nqa F1F0 (F)-ATP synthase raws li qhov pore tivthaiv tsom mus rau mutagenesis ntawm cov seem ntawm F-ATP synthase. Tshwj xeeb, nws tau pom tias matrix H + ua rau inhibition ntawm mPTP thiab ua tiav channel thaiv ntawm pH 6.5 [25, 35].

Nws tau pom tias lawv PTP thaiv yog kho los ntawm reversible protonation ofmatrix-accessible Nws residues [35]. Tsis ntev los no, H112 ntawm lub OSCP subunit tau cuam tshuam raws li nws lub luag haujlwm tshwj xeeb rau PTP thaiv los ntawm H + [25].

Txawm hais tias cov kev tshawb pom no muaj txiaj ntsig zoo txog kev ua haujlwm mPTP, lawv ua haujlwm rau ob lub hom phiaj tseem ceeb hauv kev txhawb nqa OSCP thiab ua rau F1F0(F)-ATP synthase ua cov khoom muaj peev xwm ntawm mPTP.Ntxiv cov khoom tsis sib haum xeeb suav nrog ANT, uas tuaj yeem ua lub luag haujlwm tswj hwm. los ntawm kev khi CypD thiab reconstitutinginto proteoliposomes, tsim Ca2+-activated pores zoo ib yam li cov mPTP [36, 37] thiab mitochondrial phosphatecarrier PiC [38, 39]. Yog li, cov khoom muaj peev xwm ntawm mPTPinclude ANT, PiC, thiab F1F0 (F)-ATP synthase (Daim duab 1).

Txawm hais tias nws lub luag haujlwm tsis sib haum xeeb, peb hais txog qhov muaj peev xwm ntawm F1F0 (F)-ATP synthase hauv mitochondrial permeability.F1F0 (F)-ATP synthase ntau yam kev cuam tshuam nrog cov molecules xws li CypD ua rau muaj zog mitochondrial. permeability.

Cov subunits tshwj xeeb ntawm F1F0 (F)-ATP synthase tau kawm rau lawv cov kev sib cuam tshuam nrog kev tswj hwm molecules xws li CypD. Nws tau xav tias mammalianF1F0 (F)-ATP synthase yog cov protein complex uas muaj cov hauv qab no: thaj av F1 muaj li ntawm ( )3, , δ, thiab εsubunits, uas protrudes hauv matrix thiab synthesizes / hydrolyzes ATP; ib qho F0 sector, tsim los ntawm ib lub subunit, lub c8-ring, ob daim nyias nyias-inserted -helices ntawm b subunit, thiabsupernumeraries subunits e, f, g, k, A6L, ntshav qab zib-associatedprotein hauv insulin -sensitive ntaub so ntswg (DAPIT) thiab 6.8 kDa proteolipid, uas tso cai rau H + ntws hla IMM; centralstalk complex; thiab lub peripheral stalk subcomplex muaj xws li hauv qab no: oligomycin rhiab heev conferral protein (OSCP), d, F6, thiab extrinsic -helices ntawm A6L thiab bsubunits (Daim duab 1) [40].

Daim duab 1: Prevailing qauv hais txog kev pleev ntawm mPTP raws li cov hauv qab no muaj peev xwm Cheebtsam: mammalian F1F0(F)-ATP synthase, Adenine nucleotide translocator (ANT), thiab mitochondrial phosphate carrier (PiC).

Daim duab yog redrawn andadapted raws li siv [138]. Txawm hais tias ANT thiab PiC tseem muaj qhov tsis sib haum xeeb ntawm mPTP, lawv tau pom tias yog ob qho tib si liab thiab ntsuab cov khoom sib tshooj ntawm innermitochondrial membrane (IMM).

Ib yam li ntawd, txawm hais tias F1F0 (F)-ATP synthase yog ib qho kev tsis sib haum xeeb, nws tau sau npe raws li hauv qab no. Cov subunits ntawm F0 cov khoom uas sau rau hauv ntshav muaj xws li a, e, f, g, thiab A6L. F1 Cheebtsam suav nrog thiab subunits sau npe daj thiab liab, feem.

C lub nplhaib subunit yog sau npe inblue sawv cev los ntawm lub tog raj kheej. F1 peripheral stalk yog tsim los ntawm subunits b, d, F6, thiab oligomycin sensitivityconferring protein (OSCP) sau npe sawv cev los ntawm peachrectangle, daim duab plaub xiav, thiab lub voj voog xiav, raws li.

ThemPTP yog lub ntsiab lus uas ROS, Ca2+, thiab lwm yam molecules canescape los ntawm matrix ntawm mitochondria.

OSCP thiab CypD cuam tshuam los txhawb kev qhib lawvPTP, thiab ntxiv mus, mPTP qhib tau nce ntxiv nrog kev laus thiab oxidative kev nyuaj siab [41–43]. Oxidative stress induces thetranslocation of the qog suppressor p53 to the mitochondrial matrix where it interacts with CypD to help in the form of the mPTP [44].

Zoo li oxidative stress-inducedformation ntawm mPTP, Ca2+ kuj tuaj yeem tsim cov mPTP. Nws tau pom tias soluble matrix peptidylprolyl isomerase F cyclophilin D (PPIF) koom nrog hauv Ca2+-induced qhib ntawm mPTP [15].

Kev sib cuam tshuam ntawm cov molecules uas tau hais los saum no, oxidative kev nyuaj siab, thiab Ca2+ overloading tuaj yeem hloov pauv loj heev nyob rau lub neej.

1.2. Lub luag haujlwm ntawm mPTP hauv Cellular Aging.

Ntau qhov kev tshawb fawb qhia tias kev ua kom mPTP hloov pauv nrog lub hnub nyoog hauv ntau hom cell thiab cov ntaub so ntswg. Cov no suav nrog permeabilized myofibrils hauv tib neeg [45], myocytes hauv nas [46], thiab osteocytesin nas [47].

Nws yuav tsum raug sau tseg, ua ntej sib tham txog ntau yam ntawm kev laus ntawm kev ua kom mPTP, tias Ca2+ yog tus tsim kom muaj txiaj ntsig zoo ntawm mPTP [48]. Tshwj xeeb, hais txog cov permeabilized myofibrils nyob rau hauv tib neeg, Gouspillou li al.[28] pom tias Ca2+ tuav thiab sijhawm rau mPTP qhib tau txo qis hauv cov leeg pob txha ntawm cov neeg laus ua haujlwm [45].

Txo Ca2+ khaws cia yog qhov qhia txog mPTPopenings [45]. Nws kuj tau pom tias mPTP ntawm cov laus, cov txiv neej nquag tswj tau qhov kev nkag siab zoo rau Ca2+, txhawb ntxiv lub tswv yim tias kev ua kom mPTP nce ntxiv yog qhov ua rau muaj kev laus.

Cov txiaj ntsig no tau ntxiv dag zog los ntawm kev ua haujlwm uas qhia tias oxidative puas tsuaj rau Ca2+ thauj mus rau Ca2+ xau rau hauv cytosol thiab tom qab mitochondrial matrix Ca2+ overloading, uas tom qab ntawd ua rau ua kom lub mPTP [ 49, 50] ib.

Kev ua kom lub mPTP tuaj yeem pom tau tias yog cov khoom lag luam nce ROS ntau lawm. Qhov tseem ceeb, ROS ntau lawm nce nrog hnub nyoog [51], thiab nws tau xav tias ROS ntau lawm yog nce hauv complexes I thiab III nrog inhibition of electron thauj [52]. Oxidative puas tsuaj rau mtDNAand/los yog electron thauj complexes yog pom zoo kom ua rau cov teeb meem ROS-tsim complexes.

Ib lub voj voog yog tsim nyob rau hauv uas ROS tsim los ntawm puas mtDNA thiab/los yog electrontransport complexes ntxiv puas electron transportcomplexes nrog hnub nyoog [51] (Daim duab 2).

Qhov nce hauv ROS ntau lawm nrog lub hnub nyoog yog qhov tseem ceeb vim tias kev nce mPTP ua kom muaj feem cuam tshuam nrog qib siab ntawm ROS. Qhov no yog raws li txoj kev tshawb fawb los ntawm Zorov thiab cov npoj yaig, uas pom tias ROS tsub zuj zuj hauv mitochondria ntawm cardiacmyocytes ua rau muaj zog mitochondrial permeabilitytransition thiab tso tawm ntawm ROS los ntawm mitochondria (ROS-vim ROS tso tawm) [53].

Yog li, kev sib raug zoo ntawm lub hnub nyoog, nce qib ROS, thiab nce mPTP qhib tau tsim.

Raws li yuav tau tham tom qab, ROS tso tawm los ntawm mitochondria tuaj yeem ua puas tsuaj rau cov DNA DNA thiab ua rau cov teeb liab toproapoptotic uas nce mPTP qhib [54–56]. Vim muaj cov kab lus no, kev hloov pauv hauv cov kab mob ua pa nrog kev laus yuav tsis tham ntxiv.

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