Targeting Lub Mitochondrial Permeability Transition Pore Los Tiv Thaiv Hnub Nyoog Sib Txuas Cell Ua Puas Thiab Neurodegeneration Part 3

SIRT3 ua haujlwm tiv thaiv hauv inhibiting ROS ntau lawm tab sis nws tuaj yeem ua rau deacetylate CypD thiab inhibit mPTPopening [83]. Txij li SIRT3 yog nyob ntawm NAD + qib, CypD qhib yog li ntawd kuj nyob ntawm qhov tsawg kawg nkaus hauv parton NAD + qib.

Hauv xyoo tas los no, ntau thiab ntau cov kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm NAD + qib thiab nco. NAD + yog ib qho tseem ceeb coenzyme uas tuaj yeem cuam tshuam nrog ntau yam enzymes los koom nrog ntau yam txheej txheem metabolic thiab kev tswj hwm hauv lub cev. Hauv lub cev cov txheej txheem metabolic, NAD + tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv oxidation, tiv thaiv kev mob, thiab lub zog metabolism.

Qee qhov kev tshawb fawb tshiab tau pom tias txo qis NAD + qib tuaj yeem cuam tshuam rau qee cov kab mob hauv lub paj hlwb, xws li kev paub tsis meej ntawm senile thiab Alzheimer's kab mob. Hauv cov kab mob no, kev nco tsis zoo yog ib qho mob tshwm sim heev. Yog li ntawd, tib neeg pib tshawb nrhiav kev sib raug zoo ntawm NAD + thiab cov kab mob no.

Ntau qhov kev sim tau pom tias nce qib NAD + tuaj yeem txhim kho kev nco, tshwj xeeb tshaj yog nco txog cov neeg laus. Hauv ib qho kev sim, cov kws tshawb fawb tau pub cov nas nrog cov zaub mov uas muaj NAD + thiab pom tias nas lub peev xwm kev txawj ntse tau txhim kho, zoo dua li pawg tswj hwm.

Tsis tas li ntawd, cov kev tshawb fawb kuj tau pom tias NAD + tseem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv neuronal thiab kho. Qee qhov xwm txheej ntawm kev puas hlwb neuronal, NAD + tuaj yeem txhawb cov txheej txheem autophagy los ntawm kev ua kom SIRT1, yog li tshem tawm cov kab mob bacteriophages thiab khib nyiab thiab txhawb kev kho cell thiab rov tsim dua tshiab. Neuronal kev puas tsuaj feem ntau cuam tshuam nrog kev nco, yog li NAD + tseem muaj peev xwm txhim kho kev nco.

Feem ntau, kev sib raug zoo ntawm NAD + qib thiab kev nco yog sib cais. Raws li tib neeg txuas ntxiv mus tob rau lawv cov kev tshawb fawb hauv daim teb no, kuv ntseeg tias yuav muaj ntau qhov chaw thiab muaj sijhawm los tshawb txog daim teb no yav tom ntej thiab ua kom muaj txiaj ntsig ntxiv rau kev txhim kho kev nco thiab tiv thaiv kev laus ntawm cov neeg laus. Cia peb tos ntsoov rau kev txhim kho yav tom ntej ua ke! Nws pom tau tias peb yuav tsum txhim kho kev nco. Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche muaj cov tshuaj tiv thaiv antioxidant, tiv thaiv kab mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm muaj peev xwm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv qhov tshwm sim ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.

Nyem paub ntxiv los txhim kho kev nco

Yog li ntawd, raws li NAD + concentration poob qis raws li cov khoom lag luam ntawm kev tiv thaiv txoj kev ua haujlwm, SIRT3 tsis tuaj yeem ua rau inhibition ntawm CypD-inducedmPTP qhib [81, 83].

SIRT3 cov teebmeem ib txhij ntawmROS ntau lawm thiab CypD ua rau muaj kev sib cuam tshuam ntawm ob, uas ua rau muaj kev qhib mPTP ntxiv. Raws li tau tham dhau los, qhov kev txo qis hauv SIRT3 kev ua haujlwm ua rau kev ua kom proapoptoticpathway los ntawm ROS-induced DDR [12,77]. Tshwj xeeb, p53 khi rau CypD los tsim ib qho kev ua rau mPTP qhib [44].

Yog li, ROS ntau lawm thiab CypD ua kom muaj kev sib txuas ntawm SIRT3 inhibition.Pore qhib tsis txwv rau CypD kev cuam tshuam nrog p53. Tsis ntev los no, kev sib raug zoo tau tsim los ntawm metformin, AMP kinase (AMPK), peroxisome proliferator-activated receptor- (PPAR) / mitochondria pathway, thiab CypD hauv cardiomyocytes [84].

Nws paub tias kev ua haujlwm ntawm AMPK tiv thaiv lub plawv ntawm myocardial infarction thiab lub plawv tsis ua haujlwm [84]. Yog li, vim nws tau pom tias metforminactivates AMPK, metformin tuaj yeem ua rau muaj peev xwm ua rau muaj kev tiv thaiv myocardial.

Metformin tshem tawm oxidative kev nyuaj siab-vim lub cev kev sib cuam tshuam ntawm PPAR thiab cyclophilin D (CypD), thiab kev tshem tawm ntawm cov kev cuam tshuam no cuam tshuam nrog inhibition ntawm mPTP tsim [84]. Yog li, cov tshuaj tiv thaiv myocardial ntawm metformin tau pom los sib sau ua ke ntawm mPTP.

1.4. Kev laus, Kev Txom Nyem Lub Neej, thiab Cov Kab Mob Neurodegenerative raws li cov txiaj ntsig ntawm mPTP qhib.

mPTP qhib tau ntau zaus thiab ntev dua nyob rau lub sijhawm raws li cov khoom tsim los ntawm ROS ntau lawm nrog hnub nyoog thiab tom qab ROS-vim ROS tso tawm [51, 53].

mPTP qhib ua rau muaj kev tso tawm ntawm ROS uas nyob rau hauv lem txhawb txoj kev proapoptotic ua rau qhib ntxiv [12, 54–56]. Vim yog txoj kev tiv thaiv kev vam khom ntawm NAD +, kev txo qis ntawm NAD + ua rau muaj kev cuam tshuam ntawm txoj kev tiv thaiv tawm hauv qhov cuam tshuam ntawm cov teeb liab proapoptotic mus rau qhov tsis sib haum xeeb [81, 83].

Yog li, nws yog ib qho tsim nyog los hais txog qhov cuam tshuam ntawm mPTP qhib hais txog tag nrho qhov tshwm sim ntawm kev laus. Nws tau ntev tau tuav tias ROS tsub zuj zuj ua rau muaj kev ntxhov siab rau oxidative thiab qhov tshwm sim tom qab pom ntawm kev laus [85].

Tsis ntev los no, ROS kev koom tes hauv cellular senescence tau txais kev saib xyuas tseem ceeb hauv kev laus hauv lub cev. Cellular senescence yog xav tias yuav pib los ntawm kev puas tsuaj uas ua rau DDR thiab txoj hauv kev tom ntej ua rau kev loj hlob raug ntes [86].

Kev sib sau ntawm senescent hlwb hauv cov ntaub so ntswg zoo sib xws nrog cov hnub nyoog nce, thiab cov hlwb senescent txo cov qia thiab cov xov tooj ntawm tes progenitor ua rau muaj peev xwm tsis zoo rau cov ntaub so ntswg rov ua dua [87-89].

Xav tias ROS plays lub luag haujlwm tseem ceeb hauv cellular senescence thiab mPTP plays lub luag haujlwm tseem ceeb hauv kev tso tawm ROS, nws yog li ntawd yuav ua rau mPTP pab txhawb kev loj hlob ntawm senescence.

Txawm hais tias kev paub txog kev sib cuam tshuam ntawm ROS thiab mPTP, kev ua haujlwm me me tau ua tiav txog kev sib raug zoo ntawm mPTP thiab cellular senescence. Hofer thiab cov npoj yaig tau tshawb xyuas nas ventricular subsarcolemmal (SSM) thiab interfibrillar (IFM) mitochondrial susceptibilityto Ca2+-induced mPTP qhib nrog kev laus thiab calorie txwv [90].

Lawv pom tias IFM nthuav tawm qhov ua rau muaj kev cuam tshuam ntau ntxiv rau mPTP qhib thaum muaj hnub nyoog laus dua. Kev poob qis hauv Ca2+ khaws cia tau pom nrog kev laus, tshwj xeeb tshaj yog thaum muaj hnub nyoog laus dua [90]. Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias SSM tsis tau pom cov txiaj ntsig zoo ib yam, thiab mPTP txoj kev koom tes nrog kev laus tuaj yeem nyob ntawm cov ntaub so ntswg.

SSM ib sab, cov txiaj ntsig no yuav qhia tau tias mPTP playsa lub luag haujlwm hauv kev cuam tshuam ntawm cellular senescence thiab yog li cov ntaub so ntswg, raws li pov thawj los ntawm qhov poob ntawm Ca2+ tuav.

Raws li tau piav saum toj no, kev puas tsuaj genomic pib txoj hauv cellular inducing senescence. Txij li thaum nws paub tias ROS tso tawm los ntawm mPTP muaj peev xwm inducing DDR, nws yog tseeb hais tias ib tug kev sib raug zoo ntawm mPTP qhib, induction ntawm cellularsenescence, thiab cellular thiab cov ntaub so ntswg laus muaj.Lwm lub tswv yim mechanism uas mPTP qhib rau cellular aging yog los ntawm kev nce qib. autophagy.

Thaum autophagy feem ntau xav tias yuav ua rau kom lub neej ntev dua vim nws muaj peev xwm tshem tawm cov proteins uas puas thiab cov kab mob ua haujlwm tsis zoo, nws tuaj yeem ua rau muaj kev puas tsuaj loj heev [91]. Nce autophagy shortened lifespan hauv C.

elegans tsis muaj serum/glucocorticoid-regulated kinase-1 (sgk1) vim yog nce mitochondrial permeability [91]. Tsis tas li ntawd, nas tswj sgk-1 tso tawm qis qis ntawm mitochondrial permeability, qib ntawm autophagy, thiab ib txwm ua neej nyob. Raws li cov txiaj ntsig no, sgk-1 tau qhia kom hloov kho mPTP qhib, uas nyob rau hauv lem mediatesmitochondrial permeability, autophagy, thiab lifespan [91].

Txij li thaum mitochondrial permeability tau txhim kho nyob rau hauv qhov tsis muaj sgk -1, nws tuaj yeem txiav txim siab tias kev txo qis ntawm lub neej raws li kev ua tsis zoo ntawm kev ua kom tsis muaj zog tuaj yeem yog vim muaj kev ua haujlwm ntawm mPTP.Kev tshawb fawb txog cov kab mob neurodegenerative, tshwj xeeb tshaj yog onPD, tau tshawb pom cov kev tshawb pom tseem ceeb txog mPTPopenings thiab kev laus. .

PD yog tus cwj pwm los ntawm ob qhov tshwm sim suav nrog kev poob ntawm dopaminergic neurons nyob rau hauv substantianigra [92] thiab tsub zuj zuj ntawm heev insoluble fibrillaraggregates ntawm cov protein alpha-synuclein [93].

Tsis ntev los no, Ludtmann thiab cov npoj yaig [64] tau tshawb xyuas kev sib raug zoo ntawm monomeric thiab oligomeric -synuclein encoded los ntawm cov noob SNCA thiab lawv cov teebmeem tom qab ntawm mPTPopenings thiab cellular tuag.

Thaum -synuclein nyob rau hauv nws daim ntawv monomeric txhim kho ATP synthase efficiency, raws li protein aggregation thiab tom qab tsim ntawm lub oligomericform, muaj tshuaj lom neeg ua haujlwm tau pom.

Tshwj xeeb, raws li nws cuam tshuam rau mPTP, cov oligomers ua rau xaiv oxidation ntawm ATP synthase beta subunit uas ua rau muaj qhov ua tau zoo ntawm mPTP qhib.

Qhov kev tshawb pom no yog qhov tseem ceeb asinduced pluripotent qia cell- (iPSC-) derived neurons bearing SNCA triplication tsim -synuclein aggregates uas cuam tshuam nrog ATP synthase thiab induce mPTP qhib, ua rau neuronal tuag [94].

PD yog, txawm li cas los xij, tsis yog tus cwj pwm los ntawm neuronal deathalone. Kev poob ntawm cov tshuaj tiv thaiv antioxidant (protein-disulfidereductase) glutathione (GSH), txo qis hauv mitochondrialcomplex I kev ua haujlwm, nce oxidative puas ntawm DNA, thiab nce qib hlau dawb hauv substania nigra tau sau tseg rau cov neeg mob uas raug kev txom nyem los ntawm PD [95, 96] .

Raws li tau hais ua ntej, ROS ntau lawm nce nrog lub hnub nyoog, tshwj xeeb hauv complexes I thiab III nrog inhibition ntawm electron thauj [51, 52]. Tsis tas li ntawd, ROS txuam nrog hauv mitochondria tuaj yeem ua rau ROS-vim ROS tso tawm ntawm mPTP [53].

ROS tso tawm los ntawm mitochondria candamage nuclear DNA thiab ua rau proapoptotic signals uas txhawb ntxiv mPTP qhib [54–56]. Yog li, mPTPlinks ob txheej txheem tseem ceeb cuam tshuam nrog PD: txo qis inmitochondrial complex I kev ua ua rau muaj zog mitochondrial ROS, uas nyob rau hauv lem prompts mPTP qhib thiab tom qab ROS tso tawm inducing ntau DNA puas[51–56].

Nws tseem ceeb heev uas yuav tsum nco ntsoov tias neuroinflamationis pom nyob rau hauv PD [64], thiab o ua rau extracellular acidification [33] uas nyob rau hauv lem ua rau nce ROSproduction nyob rau hauv lub cell tsav ntxiv mROS tso tawm ntawm lub matrix ntawm lub mitochondria ntawm lub mPTP [5, 34. , 35] ib.

Lub etiology ntawm PD yog complex thiab multifactorial cuam tshuam nrog ib puag ncig yam tseem ceeb, genetic susceptibility, thiab laus uas ua ke txhawb cov kab mob kev loj hlob [97].

Cov kev tshawb pom saum toj no qhia tau hais tias mPTP kuj tseem yuav muaj lub luag haujlwm tseem ceeb hauv cov kab mob ntawm PD.Age-related dysfunctions ntawm mPTP txuas mus rau thiab muaj feem ntau hauv cov hnub nyoog ntsig txog pathologies kho los ntawm ntau yam xws li mob. Kev mob plab yog ib qho tseem ceeb hauv cov kab mob ntawm AD [98], thiab neuroinflammation yog qhov ua tiav uas tshwm sim hauv PD [99].

Raws li tau hais ua ntej lawm, extracellular acidification tuaj yeem ua rau ROS ntau lawm, uas ua rau nce PT ntawm qhov qhib ntawm mPTP [59]. mPTPdysfunction kuj tseem tuaj yeem koom nrog kev nce qib ntawm AD.

Nyob rau hauv nws cov theem tom qab, AD yog tus yam ntxwv los ntawm loj heev amyloid-beta (A) deposition nyob rau hauv lub parenchyma thiab cerebrovascular phab ntsa [100, 101]. Cov kev tshawb pom tsis ntev los no qhia tau hais tias kev puas tsuaj mitochondrial hauv AD yog txuas rau A toxicity [102–105].

Qee qhov piv txwv suav nrog txo qis mitochondrial respiratorychain muaj nuj nqi [105, 106], nce mitochondrial ROS tiam [105, 107], thiab kev hloov pauv hauv mitochondrial qauv [108].

Kev sib cuam tshuam ntawm A hom nrog qee tus neeg tswj hwm ntawm mPTP yuav muaj feem cuam tshuam rau qhov kev puas tsuaj saum toj no. Tshwj xeeb, kev sib cuam tshuam ntawm A hom nrog CypDand qhov kev tswj hwm ntawm CypD qhia tau pom tias txo qis qhov pib ntawm mPTP ua kom [109].

Ib qho qauv ADmouse overexpressing ib tug mutant tib neeg daim ntawv ntawm amyloid precursor protein (mAPP) kuj tau pom los ua kom pom ntau ntau CypD [109]. Yog li, A zoo li taum tseem ceeb tus neeg nruab nrab txuas AD mus rau mPTP.

CypD yog suav tias yog ib qho tseem ceeb ntawm cov mitochondrial permeability transition pore (mPTP) tsim [4,110]. Du et al. pom tias mitochondrial muaj nuj nqi thiab kev kawm / nco tau zoo dua hauv cov nas CypDdeficient [109, 111].

Cov txiaj ntsig no qhia tias qhov pore tsim yog ib kauj ruam tsim nyog nyob rau hauv lub pathogenesis ntawm AD thiab hais tias lub ablation ntawm CypD nyob rau hauv nas muab kev tiv thaiv mus ib txhis tiv thaiv A -induced mitochondrial thiab coj cwj pwm tsis ua hauj lwm [111].

Lwm cov kev tshawb fawb tau pom tias A oligomers inducea loj nkag ntawm Ca({0}}) nyob rau hauv neurons thiab txhawb mitochondrial Ca(2+) overload thiab mitochondrial PT [112].

Qhov no tseem ceeb vim hais tias, raws li tau hais ua ntej, Ca2+ overload tuaj yeem ua rau mPTP ua kom [49, 50]. Nonsteroidal anti-inflammatory tshuaj (NSAIDs), suav nrog salicylate thiab sulindac sulfide, muaj peev xwm inhibit mitochondrial Ca2+overload los ntawm mitochondrial depolarization. Cov kev tshawb fawb no qhia txog lub luag haujlwm ntawm mPTP tsis ua haujlwm hauv cov kab mob neurodegenerative.

1.5. Muaj peev xwm kho tau kom txo tau mPTP qhib.

Cov hauj lwm yav dhau los qhia tias mPTP qhib ua lub luag haujlwm hauv kev raug mob thiab kev laus, yog li tsom cov kev kho mob txhawm rau txhawm rau txuas ntxiv thiab nquag qhib ntawm mPTP tuaj yeem pab txhawb kev ua neej ntev thiab kev noj qab haus huv (Table 1).

Raws li tau tham dhau los, PD, AD, thiab lwm yam kev mob ntsig txog hnub nyoog tau xav tias yog los ntawm cov khoom ntawm mPTP qhib. Kev tshawb fawb tsom mus rau mPTP txawm hais ncaj qha lossis tsis ncaj yog muab faib ua ob thaj chaw.

Thawj cheeb tsam koom nrog kev kho mob uas xav tau qee yam kev cuam tshuam nrog CypD, thiab thaj chaw thib ob suav nrog kev kho mob uas yuav tsum tsis muaj kev cuam tshuam nrog CypD [113].

Ntawm cov kev kho mob uas inhibit CypD, cyclosporin A (CsA) tau evoked zoo txaus siab raws li nws tau qhia cytoprotective zog nyob rau hauv cellular qauv vim nws muaj peev xwm cuam tshuam nrog kev sib cuam tshuam ntawm CypD nrog mPTP [114]. Tshwj xeeb, CsAha tau pom tias thaiv mitochondrial Ca2+ efflux thiab tso cai rau mitochondria kom khaws cov nyiaj ntau ntawm Ca2+ [115].Lub tshuab ua lub luag haujlwm kom nce Ca2+ khaws cia yog qhia ntawm mPTP kaw [45].

Cov ntsiab lus no tau txhawb nqa los ntawm Crompton thiab cov npoj yaig, uas pom tias lub peev xwm ntawm mitochondria khaws Ca2+ nyob rau hauv lub xub ntiag ntawm CsA yog vim li cas rau CsA inhibition ntawm mPTP [116]. CypD tshwj xeeb tau pom tias yog lub hom phiaj ntawm CsA [117].

mPTP qhib tau kawm nyob rau hauv ischemic reperfusion raug mob hauv nas plawv los txiav txim siab qhov ua tau zoo ntawm CsA hauv cardioprotection. Cardioprotection tau pom nyob rau hauv qhov nqaim, nruab nrab ntawm {{0}}.2 thiab 0.4 μM, raws li cov txiaj ntsig tau poob ntawm qhov siab tshaj 0.4 μM [118].

Txawm hais tias cov txiaj ntsig tau txais txiaj ntsig zoo no, qhov kev sim tshuaj ntsuam xyuas tau pom tias CsA ua tsis tau zoo los txhim kho cov txiaj ntsig kho mob thiab tiv thaiv qhov tsis zoo ntawm sab laug ventricular kho cov neeg mob nrog qhov mob anterior ST-segment elevation myocardial infarction (STEMI) [117]. Qhov no ua rau muaj lus nug hais txog kev muaj peev xwm ntawm lub hom phiaj CypD los txhawb kev tiv thaiv cardioprotective.

Nws yog qhov ua tau tias cov kev sib cav zoo li no ntawm kev kho mob cardioprotection muab los ntawm CSA tuaj yeem piav qhia los ntawm kev tswj hwm tshuaj. Txij li thaum cardioprotection tau pom nyob rau hauv ib tug nqaim ntau yam nyob rau hauv rathearts, nws yog ua tau hais tias qhov ntau npaum li cas nyob rau hauv cov kev soj ntsuam sim, 2.5 mg / kg lub cev qhov hnyav, yog tsawg heev / siab ntawm concentration [117].

Kev tshawb fawb ntxiv txhawb nqa CypD raws li lub hom phiaj siv tau cardioprotective tau ua los ntawm Parodi-Rullman li al. Oninduced myocardial infarction hauv nas [119] Lawv pom tias CypD inhibition exerts cardioprotective teebmeem nyob rau hauv reperfused tab sis tsis nyob rau hauv uas tsis yog reperfused infarcted lub siab ntawm poj niam nas, thiab cov teebmeem yog pom tsuas yog thaum mob postinfarctioninjury.

CypD tseem yog lub hom phiaj siv tau rau cov hnub nyoog ntsig txog pathologies, txawm hais tias lub sijhawm thiab kev siv tshuaj yuav tsum tau ua kom zoo dua qub thiab ua kom zoo dua los ua kom pom tseeb cov txiaj ntsig rau tus neeg mob.

CypD inhibitor, CsA derivative Nmethyl-isoleucine-4-cyclosporin (NIM811), tau raug tshawb xyuas los ua lwm txoj hauv kev kho rau CsA ib leeg. Hauv kev tshawb nrhiav los txiav txim siab qhov ua tau zoo ntawm NIM811 hauv inhibiting mPTP, nws tau pom tias ob qho tib si mitochondrialpermeability hloov pauv pib thiab apoptosis raug tiv thaiv thaum NIM811 ntxiv rau nas hepatocytes [114].

Lub peev xwm ntawm NIM811 rau txo mitochondrial permeability thiab txhim kho cell ciaj sia taus kuj tau pom nyob rau hauv cov tsiaj qauv ntawm tus txha caj qaum raug mob [120], raug mob hlwb [121], thiab hindlimb ischemia-reperfusion raug mob [122].

CypD-independent therapeutics tau txais kev saib xyuas (Table 1). Melatonin tshwj xeeb tau raug kawm raws li apotential inhibitor rau mPTP uas tsis tas yuav CypDinteraction.

Melatonin tau pom tias inhibit mPTP ua kom pom tseeb los ntawm kev txo qis mitochondrial o thiab nce Ca{0}} muaj peev xwm [123]. Qhov no tau txhawb ntxiv los ntawmAndrabi thiab. al leej twg kawm txog cov teebmeem ntawm melatonin ntawm mPTPopenings hauv nas hlwb qauv [124]. Kev tso tawm ntawm cytochrome c tau siv los ntsuas qhov pore qhib, thiab nas kho nrog melatonin pom qhov txo qis hauv cytochromec tso tawm [124].

Cov txiaj ntsig no yuav txhawb nqa qhov kev lees paub tias melatonin tiag tiag inhibit mPTP ua kom. Postmortemanalyses ntawm cerebrospinal kua qhia tau hais tias qhov txo qis hauv melatonin concentration nrog hnub nyoog [125], uas tuaj yeem ua rau txoj kev xav ua rau muaj zog mPTP qhib nrog kev laus. mPTPopenings ua rau o ntawm mitochondria, rupture ntawm sab mitochondrial membrane, thiab tom qab tso tawm ntawm intermembranous proteins [126].

Melatonin supplementation tej zaum yuav sawv cev rau ib qho kev xaiv los txwv mPTPopening nyob rau hauv cov neeg laus uas yuav muaj cov qib qis ntawm melatonin.

Ntxiv nrog rau melatonin, lwm yam CypD-ywj siab kho mob muaj xws li mitotargeted compounds (Table 1). Mitotargeted therapeutics ua haujlwm thaum tsis muaj CypDinteraction suav nrog electron scavengers, cinnamic anilides, N-phenylbenzamides, thiab isoxazoles.

Ib qho me me moleculethat ncaj qha lub hom phiaj rau mPTP yog (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide (compound 22), a cinnamic anilide uas inhibits oxidative stressand chemical crosslinker-induced mPTP qhib [127].

Lwm cov kev kho tshiab CypD-kev ywj pheej muaj nyob, muab faib rau hauv tib lub cinnamic anilide series thiab ua cov haujlwm zoo sib xws li cov khoom sib xyaw 22. Ib qho piv txwv yog GNX-4728 uas tau tswj hwm hauv tus qauv nas ntawm amyotrophic lateralsclerosis (ALS). GNX-4728 tau pom tias muaj kab mob qeeb zuj zus, txhim kho lub cev muaj zog, thiab ua kom lub neej ntev li ob npaug.

Tsis tas li ntawd, Ca2+ kev tuav pov hwm tau tsim, uas yog rov qhia txog kev kaw mPTP [128]. Hais txog N-phenylbenzamides, tus kws kho mob tseem ceeb tshaj plaws yog compound 4, (3-(benzyloxy)-5-chloro-N-(4-(piperidin-1-}ylmethyl)phenyl)benzamide) . Compound 4 induced aconcentration-dependent nce nyob rau hauv calcium retentioncapacity (CRC) ntawm permeabilized HeLa hlwb tawm tswv yim mPTP inhibition [129].

Cov isoxazole, compound 1, 5-(3-}hydroxyphenyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide, tsim cov txiaj ntsig zoo sib xws hauv cov kab mob mitochondria uas raug rho tawm. qauv. Compound 1 tau pom tias inhibitmitochondrial o tsis cuam tshuam nrog innermitochondrial membrane peev xwm [130].Electron scavengers yog microtargeted therapeutics acting nyob rau hauv tsis muaj kev sib cuam tshuam ntawm CypD.

Qee qhov kev kawm tshuaj kho mob tshaj plaws hauv pawg no suav nrog SS-31, XJB-5-131, MitoQ, EUK-8, thiab MitoTEMPO. SS-31 tuaj yeem ua kom cov cellurvival thiab txo qis hauv cov cellular ROS hauv neuronal N2A cell kho nrog t-butyl hydroperoxide (tBHP) [131]. XJB-5-131 tuaj yeem txhim kho postischemic rov qab ntawm lub siab lub ntsws, txo Ca2+- ua kom o hauv mitochondria, thiab txo cov qib totalmROS hauv cardiomyocytes [132].

Nws kuj tau pom tias XJB-5-131 txhim kho lub cev muaj zog thiab kev paub txog kev ua haujlwm hauv cov nas uas raug mob hlwb. Cov txiaj ntsig no tau pom los ntawm kev txo qis ntawm mROS thiab kev tiv thaiv tom qab ntawm cardiolipin oxidation [133]. Ob leeg MitoQand EUK-8 siv tib lub tshuab electron-scavenging raws li cov kev kho mob saum toj no.

MitoQ cov kev kho mob tau tshuaj xyuas hauv nas plawv ischemia-reperfusion raug mob thiab MitoQ txo qis cell tuag thiab txo mitochondrialdamage [134]. EUK-8 cov teebmeem tau raug tshuaj xyuas hauv presymptomatic lub plawv / cov leeg nqaij tshwj xeeb manganese-superoxide dismutase- (Mn-SOD-) cov nas tsis txaus. Nws tau pom tias EU-8 suppressed qhov kev loj hlob ntawm lub plawv tsis ua haujlwm thiab txo qis ROS ntau lawm thiab oxidative puas tsuaj [135].

Ib zaug ntxiv, thaum cov kev kho mob saum toj no tsis cuam tshuam nrog mPTP, lawv txo qis ROS qib lossis ntau lawm hauv mitochondria, uas ua rau inhibition of mPTP qhib.

MitoTEMPO tau raug tshawb xyuas raws li qhov muaj peev xwm kho tau hauv kev kho AD. Ib txoj kev tshawb fawb tsis ntev los no tau ua nyob rau hauv uas A toxicity, lub cim ntawm AD, tau ntsuas hauv thawj kab ke nas neurons. Thaum kho nrog MitoTEMPO, nws tau pom tias A-induced mitochondrialsuperoxide ntau lawm thiab neuronal lipid oxidation tau txo qis.

Tsis tas li ntawd, kev tiv thaiv kev tiv thaiv ntawm mitochondrial bioenergetics tau pom raws li pov thawj los ntawm kev khaws cia mitochondrial membrane peev xwm [136]. Cov txiaj ntsig no yuav qhia tau tias MitoTEMPO muaj peev xwm tiv thaiv kev ua haujlwm neuronal hauv AD. Thaum cov kev kho mob yav dhau los nyob rau theem kev txhim kho, ib txoj kev kho tau raug pom zoo los kho tus mob ischemic mob stroke hauv Nyiv.

Edaravone yog ib qho dawb radical scavenger uas ua rau neuroprotectiveeffects. Cov txheej txheem uas qhov no ua tiav yog zoo ib yam li lwm cov scavengers nyob rau hauv uas edaravone captures andreduces ntau dhau ROS [137]. Ib yam li ntawd, ib yam li lwm cov scavengers, cov kev kho mob ua rau kev sib raug zoo ntawm ROS thiab mPTP ua kom. Yog li, raws li ib tug byproduct ntawm edaravoneadministration, ib tug txo nyob rau hauv ROS yog pom thiab ib tug txo nyob rau hauv mPTP ua kom tshwm sim.

2. Cov ntsiab lus thiab cov lus xaus

Mitochondrial dysfunction tam sim no xav tias ua lub luag haujlwm tseem ceeb hauv cov ntaub so ntswg degeneration thiab poob ntawm kev ua haujlwm uas tshwm sim hauv ntau lub cev nrog lub hnub nyoog.

Ib qho tseem ceeb hauv cov txheej txheem no yog lub cim ntawm reactive oxygen hom nyob rau hauv mitochondria ntawm cov laus hlwb, uas yog nyob rau hauv lem txuam nrog cell tuag, senescence, thiab cov ntaub so ntswg puas. Lub mitochondrial permeability hloov pore zoo nkaus li ua lub luag haujlwm tseem ceeb hauv ROS ntau lawm nrog kev laus. Piv txwv li, txuas ntxiv qhib mPTP thiab tso tawm ntawm mROS ua rau DNA puas. Cytoprotective txoj kev yog qhib kom muaj kev puas tsuaj oxidative; Txawm li cas los xij, txuas ntxiv ua haujlwm ntawm txoj hauv kev no ua rau muaj kev cuam tshuam ntawm NAD +.

Txij li ob qho tib si PARP1 thiab sirtuin txoj kev tiv thaiv yog nyob ntawm NAD +, lawv poob lawv lub peev xwm los txwv mPTP qhib thiab inhibit mROS tso tawm thiab ntau lawm. Cov kev tshawb pom no taw qhia rau mPTP inhibition raws li qhov muaj peev xwm kho mob rau cov hnub nyoog muaj feem cuam tshuam. Mitotargeted compounds thiab cov me me xws li NIM811 muaj, tsawg kawg hauv cov qauv tsiaj, ua kom pom kev ua tiav hauv kev txhawb nqa cell ciaj sia nyob rau hauv cov chaw cuam tshuam nrog kev puas tsuaj ntawm tes xws li txha caj qaum, raug mob hlwb, thiab ischemic stroke.

Txawm li cas los xij, qhov kev thov ntawm mPTP-targeted tshuaj nyob rau hauv chaw kho mob tseem tsis pom. Qhov no yog pov thawj los ntawm CsA, uas ua tsis tau zoo los txhim kho cov txiaj ntsig kev kho mob thiab tiv thaiv tsis zoo sab laug ventricular remodeling nyob rau hauv cov neeg mob uas muaj acutemyocardial infarction. Lub tshuab hluav taws xob scavenger edaravoneremains yog ib qho ntawm cov tshuaj mPTP nkaus xwb uas tau pom zoo rau kev siv tshuaj kho mob raws li tus neeg saib xyuas neuroprotective.

Cov kev tshawb fawb yav tom ntej yuav tsum raug coj los ntawm kev tshawb nrhiav kev siv mus sij hawm ntev ntawm cov molecules me me hauv cov tsiaj laus los txiav txim siab txog lawv txoj kev loj hlob thiab kev loj hlob ntawm cov kab mob sib kis ntawm lub hlwb, musculoskeletal, thiab cov hlab plawv.

Kev tsis sib haum xeeb

Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev cuam tshuam ntawm kev txaus siab.

Kev lees paub

Cov nyiaj pab rau kev tshawb fawb no yog muab los ntawm National Institute on Aging, US National Institutes of Health (AG036675), thiab US Army Medical Research thiab Materiel CommandCDMRP Program Grant DM160252.

Cov ntaub ntawv

[1] N. Sun, RJ Youle, thiab T. Finkel, "Lub hauv paus mitochondrial ofaging," Molecular Cell, vol. 61, Nr. 5, pp. 654–666, 2016.

[2] DV Ziegler, CD Wiley, thiab MC Velarde, "Mitochondrialeffectors ntawm cellular senescence: dhau qhov dawb radical theory of aging," Aging Cell, vol. 14, nr. 1, pp. 1–7, 2015.

[3] SI Liochev, "Reactive oxygen species and the free radicaltheory of aging," Free Radical Biology & Medicine, vol. 60 ,pab. 1–4, 2013.

[4] CP Baines, RA Kaiser, NH Purcell, thiab al., "Kev poob ntawm cyclophilin D qhia lub luag haujlwm tseem ceeb rau mitochondrial permeabilitytransition hauv cell tuag," Xwm, vol. 434, Nr. 7033, pp. 658–662, 2005.

[5] RA Eliseev, G. Filippov, J. Velos, et al., "Lub luag hauj lwm ntawm cyclophilin Din the resistance of hlwb mitochondria to the permeabilitytransition," Neurobiology of Aging, vol. 28, nr. 10, pp. 1532–1542, 2007.

[6] J. Jordán, V. Ceña, thiab JH Prehn, "Mitochondrial tswj ntawmneuron tuag thiab nws lub luag haujlwm hauv neurodegenerative disorders," Phau ntawv Journal of Physiology thiab Biochemistry, vol. 5 9, nr. 2 ,pab. 129–141, 2003, ib.

[7] CP Connern thiab AP Halestrap, "Kev nrhiav cov mitochondrial cyclophilin mus rau mitochondrial puab membrane nyob rau hauv tej yam kev mob ntawm oxidative kev nyuaj siab uas txhim khu lub qhib ntawm ib tug calcium-rhiab heev uas tsis yog-specific channel," BiochemicalJournal, vol. 302, Nr. 2, nr 321–324, 1994.

[8] H. Rottenberg thiab JB Hoek, "Txoj kev ntawm mitochondrialROS mus rau kev laus khiav los ntawm mitochondrial permeabilitytransition pore," Aging Cell, vol. 16, nr. 5, pp. 943–955, 2017.

[9] DB Zorov, M. Juhaszova, and SJ Sollott, "Mitochondrialreactive oxygen species (ROS) and ROS-induced ROSrelease," Physiological Reviews, vol. 9 4, nr. 3, nr 909–950, 2014.

[10] CE Schaar, DJ Dues, KK Spilbauer, et al., "Mitochondrial thiab cytoplasmic ROS muaj qhov cuam tshuam rau kev ua neej," PLoS Genetics, vol. 11, nr. 2, tsab xov xwm e1004972, 2015.

For more information:1950477648nn@gmail.com