Insights Into The Pathogenesis Of Neurodegenerative Disease: Focus On Mitochondrial Dysfunction Thiab Oxidative Stress Part 1

Paub meej: Raws li cov pej xeem muaj hnub nyoog, qhov tshwm sim ntawm cov kab mob neurodegenerative nce. Raws li kev tshawb fawb hnyav, cov kauj ruam tseem ceeb hauv kev nthuav dav ntawm cov kab mob pathogenetic cascades tau ua thiab cuam tshuam mitochondrial tsis ua haujlwm thiab oxidative kev nyuaj siab.

Nrog rau kev txhim kho txuas ntxiv rau cov tshuaj niaj hnub thiab cov qauv kev ua neej nyob, qhov nruab nrab lub neej expectancy ntawm tib neeg tau ntev thiab ntev, uas kuj txhais tau hais tias kev laus ntawm cov pejxeem yog ntau thiab ntau serioua s. Txawm hais tias cov neeg laus yuav tsum ntsib ntau yam teeb meem kev noj qab haus huv thiab lub neej, kev nco tsis tas yuav yog ib qho ntawm cov teeb meem no.

Qhov tseeb, muaj ntau tus neeg laus uas muaj kev nco zoo heev. Lawv tuaj yeem tswj tsis tau lawv lub neej txhua hnub, tab sis kuj siv lawv lub neej ex, kev ua haujlwm los daws teeb meem. Hais txog qhov poob ntawm kev nco, ntau tus neeg xav tias qhov no yog vim muaj hnub nyoog, tab sis qhov tseeb qhov no tsuas yog kev xav tsis zoo xwb.

Cov kev tshawb fawb muaj sh yog tsis muaj kev sib txuas ncaj qha beprovides poob thiab pejxeem laus. Txawm tias hluas los yog laus, peb lub hlwb muaj peev xwm kho lawv tus kheej, tsuav yog peb cob qhia tsis tu ncua, peb tuaj yeem txhim kho peb lub cim xeeb. Kev poob ntawm kev nco ntawm cov neeg laus muaj ntau dua vim lawv lub hlwb tsis ua haujlwm tag nrho, ua rau lub hlwb poob qis.

Peb tuaj yeem siv qee qhov kev ntsuas los txhawb peb lub cim xeeb, xws li kev tawm dag zog peb lub hlwb los ntawm ntau yam haujlwm xws li kev nyeem ntawv, sau ntawv, pleev xim, mus ncig thiab kev sib raug zoo. Tsis tas li ntawd xwb, peb tseem tuaj yeem ua tib zoo saib xyuas kev noj zaub mov thiab kev ua neej, xws li tswj kev pw tsaug zog zoo, noj zaub mov kom zoo, thiab zam kev coj cwj pwm tsis zoo xws li haus luam yeeb lossis haus cawv.

Yog li ntawd, peb yuav tsum tsis txhob hais txog qhov poob ntawm lub cim xeeb vim kev laus ntawm cov pej xeem, tab sis yuav tsum muaj zog ntau dua hauv kev tawm dag zog thiab tswj lub hlwb. Los ntawm kev txhim kho peb lub cim xeeb, peb tuaj yeem tiv thaiv peb txoj kev noj qab haus huv thiab lub neej dawb. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco, vim Cistanche yog cov khoom siv tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Cov nyhuv 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

Txawm li cas los xij, cov kev kho mob muaj nyob rau hauv Alzheimer's disease, Parkinson's disease, thiab amyotrophic lateral sclerosis yog cov tsos mob, muab cov txiaj ntsig me me thiab, feem ntau, qeeb qeeb ntawm kev loj hlob ntawm tus kab mob.

Txawm hais tias nyob rau hauv preclinical chaw, cov tshuaj tsom mus rau mitochondrial tsis ua hauj lwm thiab oxidative stressyielded txhawb cov kev tshwm sim, soj ntsuam kev sim ua tsis tau tejyam los yog tau inconclusive. Nws yog qhov zoo li tias los ntawm lub sijhawm kuaj mob, cov kab mob pathogenetic cascades puv puv thiab cov xov tooj tseem ceeb ntawm cov neurons twb tau degenerated, ua rau nws ua tsis tau rau mitochondria-targeted lossis antioxidant molecules kom nres lossis thim rov qab cov txheej txheem.

Txog thaum kev tshawb fawb ntxiv yuav muab cov molecules muaj txiaj ntsig zoo dua, kev noj qab haus huv txoj kev ua neej, nrog ntau cov khoom noj antioxidants thiab kev zam ntawm exogenous oxidants yuav ncua qhov pib ntawm neurodegeneration, thaum cov neeg mob hauv tsev neeg yuav tau txais txiaj ntsig los ntawm kev ntsuam xyuas caj ces thiab kev kho mob hnyav pib nyob rau theem preclinical.

Ntsiab lus: mitochondrial tsis ua haujlwm; oxidative kev nyuaj siab; antioxidants; Alzheimer tus kab mob; Parkinson tus kab mob; amyotrophic lateral sclerosis.

1. Taw qhia

Cov neeg laus koom nrog ntau qhov kev tsis txaus ntawm lub cev thiab qhov sib txawv ntawm kev paub tsis meej, kuj yog qhov tseem ceeb rau cov kab mob neurodegenerative xws li Alzheimer'sdisease (AD), Parkinson's disease (PD), lossis amyotrophic lateral sclerosis (ALS) [1].

Los ntawm cov nyiaj txiag ntau ntawm kev tshawb fawb tsom rau kev daws cov txheej txheem ntawm kev laus thiab neurodegeneration ob peb daim ntawm cov duab dhos ua si tau tshwm sim, tab sis peb tseem muaj txoj hauv kev ntev mus nkag rau tag nrho daim duab. Txawm li cas los xij, nws zoo nkaus li tias oxidative puas tsuaj tshwm sim los ntawm freeradicals thiab mitochondrial tsis ua haujlwm ua lub luag haujlwm tseem ceeb hauv ob qho tib si.

2. Kev laus li qub

Kev laus ntawm lub hlwb tshwm sim ntawm molecular, cellular, thiab histological qib [2]. Nws koom nrog qis qis ntawm cov kev ua haujlwm neuronal metabolic, hloov pauv hloov maj mam hauv cov qauv neuronal hauv ntau lub hauv paus hauv lub cev, nrog rau kev ua kom lub cev tsis zoo, cytoskeletal abnormalities, tsub zuj zuj ntawm fluorescent pigments, thiab reactive astrocytes thiab microglia [3,4].

Kev tshawb fawb cov ntsiab lus mus rau lub hypothalamus raws li pib thiab tswj kev maj mam poob ntawm lub zog metabolism ntawm tag nrho lub cev [5,6]. Los ntawm kev tso tawm ntawm cov neurohormones, kev sib txuas nrog cov kab ke endocrine, thiab kev kwv yees ntawm orexinergic nucleus mus rau lub reticular activatingsystem [5], lub hypothalamus tswj cov theem kev ntxhov siab, metabolism, pw tsaug zog, thiab cuam tshuam cov kev xav ntawm lub neej zoo thiab tsim kom muaj kev sib raug zoo ntawm kev sib raug zoo. 7–9] ib.

Degeneration ntawm suprachiasmatic nucleus kuj tseem tuaj yeem ua rau circadianrhythm teeb meem thiab pw tsaug zog tsis zoo [10–12]. Kev txwv kev pw tsaug zog tuaj yeem ua rau cov khoom siv tshuaj lom neeg cov khoom pov tseg rau hauv cov khoom siv tshuaj lom thiab txwv cov neurogenesis hauv lub hlwb laus, ua rau lub voj voog vicious uas txhawb cov txheej txheem neurodegenerative [13].

Lwm yam tseem ceeb ua rau txo qis cov metabolism hauv lub hlwb. Cerebralmetabolism tsuas yog tso siab rau qhov tsis tu ncua ntawm cov piam thaj thiab cov pa oxygen los ntawm cov ntshav, thiab, rau qhov txwv, ntawm lactate [14].

Neuronal qabzib uptake yog kho los ntawm glucose transporters (GLUTs), tom qab ntawd nws hloov mus rau hauv qabzib -6-phosphate (G6P) los ntawm hexokinase. Yog li, qhov muaj ntawm ATP, nyob ntawm seb cov pa oxygen thiab mitochondrial oxidative phosphorylation (OXPHOS), cuam tshuam nrog cov piam thaj uptake [5,15] .OXPHOS ua rau muaj txiaj ntsig ntau dua ntawm ATP piv rau glycolysis [16,17].

Hauv kev laus, txo cov metabolism tuaj yeem tshwm sim los ntawm mitochondrial dysfunction thiab txo ATP synthesis, nrog rau kev hloov pauv ntawm cov hlab ntsha uas ua rau muaj cov pa oxygen tsawg.

Kev siv hluav taws xob siab ntawm tes hauv lub paj hlwb, siv rau kev sib kis ntawm synaptic (nyob ib ncig ntawm 80% ntawm lub zog noj ntawm lub hlwb) [18,19], synaptogenesis, andsynaptic pruning [18,20] koom nrog ntau tus nqi ntawm kev tsim cov pa oxygen reactive. hom kab mob feem ntau yog los ntawm electrons tawm los ntawm mitochondrial electron thauj saw (ETC).

Ntau dhau ntawm cov dawb radicals tsis tuaj yeem ua rau tsis zoo los ntawm kev tiv thaiv antioxidant thiab ua rau oxidative kev nyuaj siab, cuam tshuam rau kev laus txij li xyoo 1950, thaum Harman tau hais tias dawb radical-induced kev puas tsuaj ntawm biomolecules, xws li cov protein, lipids, thiab DNA, ua rau muaj kev cuam tshuam ntawm lawv cov biochemical thiab physiological muaj nuj nqi hauv kev laus [21]

Qhov tseeb, kev tshawb fawb tau pom tias muaj kev hloov pauv ntawm phospholipids hauv lub hlwb ntawm cov neeg laus thiab cov tsiaj txhu ua ke nrog nce malondialdehyde (ib qho cim ntawm lipid peroxidation) tiam, uas tsim cov deposits txuas nrog intraneuronal lipofuscin [22], thiab elevatedcarbonyl residues ntawm protein (Oxidues). 23] ib.

Tsis tas li ntawd, kev laus txo qis theantioxidant tiv thaiv kab ke, xws li astrocytic glutathione system [24], uas ntxiv zog oxidative kev nyuaj siab [2] .Mitochondria tau dhau los ua ntau yam kev hloov pauv hnub nyoog xws li fragmentation lossis o [25], nce mitochondrial DNA (mtDNA). ) oxidative kev puas tsuaj [26], nthuav tawm kev ua haujlwm ntawm cov kab mob ua pa [27] thiab calcium homeostasis [28].

Cov kev hloov pauv no cuam tshuam txog kev txo qis ntawm intracellular NAD + qib uas cuam tshuam kev ua haujlwm ntawm NAdependent enzymes xws li sirtuins (SIRT) thiab histone deacetylases [29,30]. Sirtuins yog cov evolutionary conserved enzymes koom nrog hauv txoj cai ntawm lifespan thiab agingin ntau yam kab mob, los ntawm cov poov xab mus rau tsiaj txhu [31].

Hauv cov tsiaj nyeg, SIRT 3, 4, thiab 5 nyob hauv mitochondria, SIRT 2 hauv cytosol, thiab SIRT 1, 6, thiab 7 nyob hauv lub nucleus [32]. Kev tshawb fawb tau pom tias SIRT 1, feem ntau hauv hypothalamus, yog ib qho tseem ceeb hauv kev tswj kev laus thiab kev ua neej nyob ntev hauv cov kab mob mammalian [33,34].

Shortening ntawm telomeres, uas txhawb cov chromosomal stability thaum lub sij hawm cell replication [35], yog thawj zaug disregarded raws li muaj ib tug tseem ceeb cawv nyob rau hauv lub hlwb txij li thaum neurons yog tseem ceeb postmitotic hlwb uas tsis replicate.

Txawm li cas los xij, qhov kev pom no tau sib tw los ntawm kev ua kom pom lub voj voog ntawm tes hauv 10-20% ntawm cov neurons hauv lub cortex ntawm lub hlwb kev laus thiab hauv AD [36,37], nrog rau muaj cov kab mob neural qia hlwb hauv subventricular thiab subgranular zones, hauv choroid plexuses thiab meninges [38] Tsis tas li ntawd, glial hlwb (tshwj xeeb tshaj yog microglia) ua dua tshiab, nrog cov telomeres maj mam luv tom qab txhua lub cellular replication [39].

Kev laus induces kuj muaj inflammatory phenotype thaum lub sij hawm uas, nyob rau hauv teb rau kev hloov thiab DNA puas, nuclear factor-κB (NF-κB) pib transcription ntawm qog nqaij hlav factor- (TNF- ) thiab ntau yam inflammatory interleukins (IL-1 , IL. -6, IL-8) [40].

ROS muaj lub luag haujlwm tseem ceeb hauv cov txheej txheem no, txij li lawv phosphorylate thiab degrade IκB, uas khi rau thiab tsis ua haujlwm NF-κB [41]. Tsawg tus nqi ntawm ROS pib ua kom muaj sia nyob signalingcascades, lub tshuab ua haujlwm NF-κB suppressing c-Jun N-terminal kinases (JNKs) thiab apoptosisand upregulating antioxidant thiab anti-apoptotic genes xws li manganese superoxidedismutase (MnSOD) [42].

Txawm li cas los xij, ROS siab ntau ua rau NF-κB los ntawm cov protein kinases thiab pib txoj kev nyuaj siab ntawm tes. Kev puas tsuaj neurons hloov theionic tshuav nyiaj li cas hauv qhov chaw nruab nrab thiab ua rau cytokine tso tawm, yog li ua kom microglia [43,44].

Txawm hais tias TNF- muaj lub luag haujlwm tseem ceeb hauv kev kawm thiab synaptic plasticity [45], kev ua kom microglial ntau dhau yuav ua rau cov synapses thiab kev ua haujlwm tsis zoo, cov yam ntxwv ntawm kev laus thiab neurodegeneration [46].

Tsis tas li ntawd, cov lus teb inflammatory ua rau lwm yam kev hloov pauv, xws li teeb liab transducer thiab activator oftranscription (STAT-1) thiab peroxisome proliferator-activated receptor-gamma (PPAR), tom kawg ua lub luag haujlwm tseem ceeb hauv mitochondrial biogenesis [47] .

Yog li ntawd, secretoryphenotype txuam nrog senescence (SASP), tshwj xeeb tshaj yog nyob rau hauv astrocytes, tuaj yeem ua rau muaj ntau yam kab mob neurodegenerative [48].

3. Mitochondria hauv hlwb

Kev ua haujlwm siab ntawm lub paj hlwb feem ntau yog nyob ntawm oxidative phosphorylation rau ATP ntau lawm. Txawm li cas los xij, mitochondria siv lwm cov haujlwm tseem ceeb hauv lub hlwb thiab.

Qhov kev taw qhia tas mus li ua rau muaj kev hloov pauv tsis tu ncua hauv cytosolic calcium concentrations thiab mitochondria hauv kev koom tes nrog endoplasmic reticulum muaj lub luag haujlwm tseem ceeb hauv kev tswj cov neurotransmission los ntawm buffering calcium hauv presynaptic terminals thiab tswj cov qib somato-dendritic calcium [49,50]. Ntxiv mus, mitochondria regulatecell voj voog thiab tswj cell tuag [51].

Txhawm rau ua kom tiav cov haujlwm sib txawv no, kev saib xyuas ntawm mitochondrial Fitness yog qhov tseem ceeb, yuav tsum muaj kev tswj xyuas zoo [52], ua tiav los ntawm mitochondrial biogenesis thiab fission (kev sib cais ntawm ib leeg organelle rau ob lossis ntau tus ntxhais organelles, qhov tseem ceeb rau kev faib tawm los yog loj hlob hlwb nrog. Tus naj npawb txaus ntawm mitochondria), fusion (ib txheej txheem los ntawm cov mitochondria cov khoom tseem ceeb), thiab mitophagy (tshem tawm ntawm mitochondria puas ua ntej lawv mus rau apoptosis ntawm tag nrho cov cell) [53,54].

Tsis tas li ntawd, mitochondria yuav tsum yog traffickedalong axons los muab lub zog thoob plaws lub axon [2].

3.1. Mitochondrial Respiratory Chain thiab ROS Production

Lub mitochondrion muaj ib tug spongy txheej mitochondrial membrane (OMM), uas tso cai rau free txav ntawm me me ions thiab uncharged molecules, thiab ib tug impermeable puab mitochondrial membrane (IMM), uas envelops lub mitochondrial matrix.

Nruab nrab ntawm IMM thiab OMM nyob qhov chaw nruab nrab [55]. Lub mitochondrial electron transportchain (ETC) muaj ntau cov protein complexes nyob rau hauv lub IMM uas siv theelectrons tshem tawm los ntawm kev txo nicotinamide adenine dinucleotide (NADH) thiab flavinadenine dinucleotide (FADH2) los ntawm lub voj voog Krebs mus twj protons los ntawm matrix rau hauv qhov chaw, nyob rau hauv lub sij hawm. tsim kom muaj peev xwm gradient hla IMM, uas yuav siv rau hauv cov kauj ruam kawg ntawm OXPHOS los ua ke ATP [56].

Yuav kom ua haujlwm tau zoo, cov complexes yuav tsum tau sib sau ua ke los ntawm folded IMM (mitochondrial cristae) rau hauv cov qauv tshwj xeeb [57]. Txawm tias nyob rau hauv ib txwm muaj mob, 1-2% ntawm tag nrho cov pa oxygen noj cov pa tawm thiab tsim ROS [58].

Yam tsawg kawg yim mitochondrial sites muaj peev xwm tsim tau ROS, nrog complexes I, II, thiab III yog lub ntsiab contributors [55,59].Los ntawm lipid peroxidation, protein oxidation, thiab DNA puas, lub generated ROS yuav ua rau hloov mitochondrial muaj nuj nqi thiab nce tus nqi. ntawm ROS ntau lawm, culminating indegeneration ntawm neurons [60,61].

3.2. Mitochondria thiab Cellular Calcium Homeostasis

Calcium koom nrog ntau yam kev ua haujlwm neuronal, xws li kev sib txawv, vesicle release and synaptic transmission, or cell death and survival [62,63]. Kev hloov pauv hloov pauv hauv cytosolic Ca2+ ua raws li tus xa xov thib ob.

Dawb cytosolic Ca2+ qib yog nyob rau hauv nanomolarranges, thaum cov qib extracellular yog millimolar. Calcium influx tshwm sim los ntawm ligandoperated los yog voltage-gated calcium channels (VGCCs), tab sis Ca2+ kuj tuaj yeem raug tso tawm los ntawm cov khw muag khoom intracellular Ca2+, ntawm cov endoplasmic reticulum (ER) muaj ib qho pivotalrole [64]. Agonist khi rau inositol 1,4,5-triphosphate (IP3) receptors lossis rau ryanodinereceptors (RyRs) ua rau tso tawm Ca2+ los ntawm ER [65].

Txawm li cas los xij, txhawm rau kom nce cytosolic Ca2+ luv luv, calcium yuav tsum tau tshem tawm sai sai los ntawm calciumefflux, khi rau Ca2+-buffering proteins [66], los yog uptake mus rau ER los yog mitochondria [62] .

Ca2+ efflux ua tiav los ntawm plasma membrane Ca2+-ATPase, uas tso Ca2+ tawm tsam cov concentration gradient thaum hydrolyzing ATP, thiab Na+/Ca2+ exchanger(NCX ), uas tso siab rau sodium gradient rau extrude Ca2+ [67].

ER Ca2+ uptake yog ua los ntawm ATP-dependent sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) [68], thaum mitochondrial Ca2+ uptake yog kho los ntawm voltage-dependent anion-selective channelproteins (VDCAs), uas kho Ca2+ hloov mus rau hauv qhov chaw nruab nrab, los ntawm qhov chaw IMM-nyob mitochondrial Ca2+ uniporter (MCU) ntxiv cov calcium mus rau hauv mitochondrial matrix.

Nce hauv mitochondrial calcium qhib ETC dehydrogenases thiab ATP ntau lawm [69]. Txawm li cas los xij, calcium ntau dhau tuaj yeem hloov pauv lub peev xwm mitochondrialmembrane, qhib lub mitochondrial permeability hloov pauv pore (MPTP), thiab ua rau cytochrome c tso [70].

Xws li, mitochondrial Ca2+ concentrations yuav tsum tau kho kom zoo.

Ib mitochondrial Na+/Ca2+ exchanger nyob rau hauv IMM, thiab hu ua NCLXvim nws kuj muaj peev xwm pauv Li + rau Ca2+, extrudes Ca2+ los ntawm mitochondrialmatrix los ntawm kev siv cov electrochemical gradient ntawm Na+[71], thaum los ntawm interemmbranespace Ca2+ yog extruded los ntawm Na+/Ca2+ exchanger 3 thiab VDACs [72]. Daim duab 1 qhia txog cov txheej txheem koom nrog hauv cellular calcium homeostasis.

Daim duab 1. Intracellular calcium homeostasis. Cellular Ca2+ influx yog kho los ntawm voltage-gated calcium channels (VGCC), ligand-gated calcium channels (LGCC), thiab, tshwj xeeb, los ntawm kev rov ua haujlwm ntawm sodium / calciumexchanger (NCX).

Tsis tas li ntawd, Ca2+ tuaj yeem raug tso tawm los ntawm ER tom qab inositol-1,4,5-triphosphate (IP3) binding tospecific receptors (IP3R) lossis ryanodine receptors (RyR).

IP3 yog tsim los ntawm kev khi ntawm ligands rau plasmalemmal Gprotein-coupled receptors, uas ua kom phospholipase C kom tshem tawm phosphatidylinositol 4, 5-biphosphate, ua rau tus xa xov thib ob IP3.

Tshaj cytosolic calcium raug tshem tawm los ntawm efflux los ntawm NCX thiab plasma membraneCa2+ ATPase (PMCA) thiab nkag mus rau hauv ER los ntawm sarcoendoplasmic reticulum Ca2+-ATPase (SERCA).

Mitochondria bufferscytosolic calcium los ntawm mitochondrial calcium uniporter (MCU) thiab extrudes tshaj Ca2+ los ntawm Na+/Ca2+exchanger (NCLX). Tsis tas li ntawd, cytosolic Ca2+ binding proteins (CBP) ua raws li cov teeb liab transducers.

Hauv kev tswj cov intracellular Ca2+ concentrations, mitochondria cuam tshuam nrog theER los ntawm mitochondria-associated ER membranes (MAMs) [73], microdomains qhov twg OMM tsuas yog 10-100 nanometers sib nrug ntawm ER [74,75].

Cov cheeb tsam no yog enriched ininositol 1,4,5-triphosphate receptors (IP3Rs) [76] uas tsim cov kev ua haujlwm nrog VDACs los ntawm ib tug chaperone, Grp75 (glucose-regulated protein 75), belongs rau heatshock protein 70 tsev neeg [77 ].

IP3R-Grp75-VDAC complexes tswj Ca2+ hloov ntawm ER mus rau mitochondria [74]. Lub apposition ntawm ER rau mitochondria yog tswj los ntawm phosphofurin acidic pawg sorting protein 2 (PACS2) [78]. Txo qhov chaw sib cuag ntawm ER thiab mitochondria tshwm sim los ntawm PACS2 tshem tawm ua rau mitochondrial fragmentation thiab apoptosis [79].

PACS2 ua haujlwm txuas nrog phosphatidylserine synthase-1 (PSS1), ib qho enzyme nyob hauv MAMs uas kho qhov hloov ntawm lipids ntawm ER thiab mitochondria [80]. PACS2 thiab PSS1 tau pom muaj kev tswj hwm hauv AD transgenic nas nrog rau cov neeg mob ashuman nrog lig pib AD [74,81]. Ob peb lwm yam khoom ntawm MAMs koom nrog calcium homeostasis thiab signaling cascades tau piav qhia, xws li:

- Bap31 (B cell receptor-associated protein 31), uas cuam tshuam nrog OMM protein Fis1 [82];

- VAPB (Vesicle-associated membrane protein-associated protein B), uas cuam tshuam nrog OMM protein tyrosine phosphatase-interacting protein 51 [83];

- Sig-1R (Sigma non-opioid intracellular 1- receptor 1), tus kws kho mob uas khi Grp78; nyob rau hauv ER kev ntxhov siab, Grp78 dissociates los ntawm ER lipid rafts thiab ua kom cov lus teb tsis muaj protein ntau (UPR) [ 84,85];

- Protein kinase-zoo li endoplasmic reticulum kinase (PERK), uas, thaum activatedreduces protein synthesis kom txog thaum cov protein ntau unfolded cleared [86].

3.3. Mitochondrial Dynamics

Mitochondria yog cov organelles muaj zog, muaj peev xwm hloov kho lawv tus lej, cov duab, qhov loj me, thiab txoj haujlwm hauv cytoplasm los ntawm kev ua tib zoo ntsuas ntawm ob txoj kev sib txawv: mitochondrial fusion thiab fission [87].

Fission yog tswj los ntawm ob lub proteins: Drp1 (dynamin-txog /-zoo li protein 1) thiab Dnm2 (dynamin 2) [88]. Thawj kauj ruam yog qhwv ntawm endoplasmic reticulum nyob ib ncig ntawm lub mitochondria thiab txo txoj kab uas hla ntawm tom kawg los ntawm 300-500 nm mus txog 150 nm [89]. Lub koom haum spatial ntawm replicating mtDNA nrog ER-mitochondriacontact sites piav qhia txog mtDNA kev faib tawm hauv cov khoom siv replicating [90].

Ua raws li cov kauj ruam no, cov cytosolic protein Drp1 raug xaiv mus rau qhov chaw uas twb muaj lawm constriction ntawm OMM thiab khi rau phospholipid membrane los ntawm adapter proteins xws li MFF (mitochondrial fission factor) thiab mitochondrial dynamics proteins 49 thiab 51 (MiD49 thiabMiD51) [91]

Tom qab Drp1 nrhiav neeg ua haujlwm, lub nplhaib zoo li cov qauv tsim nyob ib ncig ntawm mitochondria [92], tom qab ntawd GTP hydrolysis potentiates lub constriction ntawm mitochondrialmembrane [87].

Cov kauj ruam kawg yog kev nrhiav neeg ua haujlwm ntawm Dnm2, GTPase uas sib sau ua ke ntawm qhov chaw cim thiab ua tiav cov txheej txheem fission [93]. Kev txwv thiab kev faib ntawm IMM yog calcium-dependent thiab tshwm sim ntawm ER-mitochondria cov chaw sib cuag, tej zaum txawm ua ntej Drp1 recruitment [94].

Mitochondrial fusion yog cov txheej txheem rov qab, uas cov membranes ntawm ob lub mitochondria fuse, ua rau ib qho mitochondrion thiab tso cai rau kev sib koom ntawm cov khoom tseem ceeb ntawm ob lub cev.

Cov txheej txheem yog tswj los ntawm ob lwm cov proteins nrog GTPase kev ua, Mfn1 thiab Mfn2 (mitofusins ​​1 thiab 2) rau fusion ntawm OMM, thaum fusion ntawm IMM yog tswj hwm ntawm lwm GTPase, OPA1 (optic atrophy 1) [95].

Tom qab ob lub mitochondria (kev kho los ntawm GTP domains), ob lub OMMs uas nyob ib sab nce lawv qhov chaw sib cuag nrog lawv cov fusion vim GTP hydrolysis, tom qab hloov pauv, thiab oligomerization ntawm Mfns [96].

Tom qab OMMfusion, IMM fusion yog kho los ntawm IMM-inserted OPA1, uas tuaj yeem cleaved los ntawm twomembrane-bound metalloproteases, OMA1 thiab YME1L, uas ua rau ob lub siab molecular hnyav tawg (L-OPA1) thiab peb ntu luv (S-OPA1) [97] .

Kev sib cuam tshuam ntawm L-OPA1 nrog cardiolipin, tso rau hauv IMM, yog qhov tseem ceeb rau kev tsav tsheb membrane fusion [98].Qhov sib npaug ntawm OMA1 lossis YME1L cleavage ntawm OPA1 tswj mitochondrial fission [99].

Stimulation of OXPHOS induces YME1L cleavage of OPA1 and mitochondrialfusion, while OPA1 cleavage by OMA1 is a stress response, and may induce mitochondrialfragmentation as well [87].

For more information:1950477648nn@gmail.com