Insights into the Pathogenesis Of Neurodegenerative Disease: Focus On Mitochondrial Dysfunction Thiab Oxidative Stress Part 2

Ntau qhov kev hloov kho tom qab kev txhais lus kuj tseem tswj cov mitochondrial dynamics. Drp1phosphorylation tuaj yeem ua rau muaj kev sib cais lossis fusion nyob ntawm qhov chaw phosphorylation [100,101].

Nrog rau kev txhim kho txuas ntxiv ntawm neuroscience, ntau thiab ntau cov kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm mitochondrial dynamics thiab nco, uas muaj lub ntsiab lus zoo thiab kev vam meej.

Mitochondria yog lub cev tseem ceeb hauv cov hlwb, muaj ob lub luag haujlwm tseem ceeb: ib qho yog muab lub zog rau cov hlwb, thiab lwm yam yog tswj hwm kev loj hlob ntawm tes thiab kev ua neej nyob. Kev ua haujlwm ntawm mitochondria tsis yog tsuas yog cuam tshuam nrog kev noj qab haus huv ntawm tes, tab sis kuj tseem cuam tshuam nrog kev noj qab haus huv ntawm tib neeg lub cev. Tib neeg nco yog ib tug ntawm lawv.

Cov kev tshawb fawb tau pom tias hauv tib neeg lub hlwb, ntau qhov kev hloov pauv tau tshwm sim hauv mitochondrial dynamics, xws li nce mitochondrial ntom, mitochondrial migration, thiab mitochondrial regeneration. Cov kev hloov no tsis tsuas yog cuam tshuam txog kev noj qab haus huv ntawm cov neurons hauv lub hlwb tab sis kuj tseem cuam tshuam nrog kev txhim kho ntawm lub hlwb nco.

Tshwj xeeb, mitochondrial dynamics tuaj yeem txhawb cov ntaub ntawv xa mus ntawm lub hlwb neurons, yog li txhawb kev tsim, sib sau ua ke, thiab rov ua dua tshiab ntawm kev nco thiab kev kawm. Tsis tas li ntawd, kev ua kis las hnyav thiab lwm yam kev ua kis las tuaj yeem txhawb kev nce ntawm mitochondrial ntom ntom, yog li txhim kho lub hlwb kev nco thiab kev txawj ntse.

Yog li ntawd, peb yuav tsum koom nrog qee yam kev ua ub no uas muaj txiaj ntsig zoo rau lub cev, xws li kev tawm dag zog, qoj ib ce, txhim kho kev noj zaub mov zoo, thiab lwm yam, txhawm rau txhawb kev loj hlob ntawm mitochondrial dynamics thiab txhim kho kev nco thiab kev txawj ntse. Nyob rau tib lub sijhawm, peb kuj yuav tsum tau saib xyuas kom so, txo kev ntxhov siab, tswj kev noj qab haus huv zoo, thiab yog li mob siab kho lub neej yav tom ntej.

Hauv cov ntsiab lus, muaj kev sib raug zoo ntawm mitochondrial dynamics thiab nco. Kev ua neej nyob thiab kev noj qab nyob zoo yog qhov muaj txiaj ntsig zoo rau kev txhim kho mitochondrial dynamics, yog li txhim kho lub hlwb kev nco thiab kev txawj ntse. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche muaj cov tshuaj tiv thaiv antioxidant, tiv thaiv kev laus, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidative thiab inflammatory teb nyob rau hauv lub hlwb, yog li tiv thaiv kev noj qab haus huv ntawm lub hlwb. 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 txoj hauv kev los txhim kho lub hlwb

Phosphorylation ntawm MFF nce Drp1 recruitment, thiab tom qab mitochondrial fission [102], thaum ubiquitination ntawm acetylated Mfn1 txhawb nws cov proteasomal degradation [103]; phosphorylation ntawm Mfn1 los ntawm ERK inhibits mitochondrial fusion, txhawb kev apoptosis [104].

Cov xeev tshwj xeeb kuj tseem tswj hwm qhov sib npaug ntawm ob txoj haujlwm no. Thaum kev tshaib kev nqhis ua rau fused thiab elongated mitochondria, ib puag ncig muaj kev noj qab haus huv yog nrog los ntawm fragmented mitochondria [105,106].

3.4. Autophagy

Autophagy yog lwm kauj ruam tseem ceeb hauv kev tswj hwm qhov sib npaug ntawm cov proteinsynthesis thiab tshem tawm, organelle biogenesis, thiab degradation, yog li txhawb nqa cellularhealth [107]. Raws li yuav ua li cas lub hom phiaj cargo xa mus rau degradation tolysosomes, autophagy tuaj yeem muab faib ua [107,108]:

- Macroautophagy, nyob rau hauv uas lub autophagosome, ob-membraned vesicle, cov ntaub ntawv, thiab fuses nrog lysosomes tom qab uas lawv cov ntsiab lus yog degraded los ntawm acidic hydrolases ntawm lysosomes;

- Microautophagy, txheej txheem thaum lub sij hawm uas lysosomes qhwv ib ncig ntawm ntau yam cytosoliccompounds uas degraded tom qab involution ntawm daim nyias nyias [109];

- Chaperone-mediated autophagy, tus txheej txheem thaum lub sij hawm cov chaperones khi rau puas cov protein thiab receptors ntawm lub lysosomal membrane, ua raws li los ntawm translocation ntawm cov protein mus rau hauv lub lysosome rau degradation [110].

Autophagy rau puas mitochondria tseem hu ua mitophagy. Thawj kauj ruam mitophagy pib yog tsim ntawm ib qho kev sib cais membrane, lub autophagosome, ntseeg tau los ntawm MAMs, daim nyias nyias ntawm ER, los yog plasma membrane [111,112], ua raws li los ntawm kev ua kom lub pre-initiation complex, muaj ULK1 (Unc {{ 4}}zoo li kinase1, Atg 13 thiab 101 (autophagy-related proteins), thiab FIP200 (focal adhesion kinase familyinteracting partner 200) [113]. beclin1, Atg 14, autophagy, thiab beclin 1 regulator (AMBRA1), nrog rau vascular protein sorting 34 thiab 15 (Vps 34 thiab 15) los tsim phosphatidylinositol3-phosphate (PI3P).

Pi3P tseem hu ua qhov pib ua haujlwm [114]. Tom qab ua kom tiav, ob qho tib si complexes hloov mus rau qhov chaw nucleation ntawm phagophore [108]. PI3P tau lees paub thiab cuam tshuam nrog lwm cov protein nyob hauv IM, xws li WD rov ua cov protein sib cuam tshuam nrog phosphoinositide (WIPI) thiab FYVE domain-muaj cov proteins [115] thiab ua rau cov kab mob sib txuas ntawm Atgs ntawm phagophore, ua rau cov cleavage ntawm pro-LC3. (lub teeb saw 3) los ntawm Atg4 rau LC3-I, hloov pauv ntxiv los ntawm phosphatidylethanolamine toLC3-II, thiab ua rau elongation thiab kaw ntawm daim nyias nyias [116,117].

Υaminobutiric acid hom A-receptor-associated protein (GABARAP) thiab GABARAP-like1 protein (GABARAPL1) ntseeg tau ua lub luag haujlwm zoo sib xws nrog LC3 hauv autophagosomeexpansion [118].

Lub signaling protein mTOR (mammalian lub hom phiaj ntawm rapamycin) muaj zog modulates autophagy. Inhibition ntawm mTOR, raws li tshwm sim nyob rau hauv kev tshaib kev nqhis, dephosphorylates thiab activates Atg13, igniting cov txheej txheem mitophagy [119].

Thaum cov khoom loj hlob thiab cov cellularnutrients muaj ntau, mTOR phosphorylates Atg 13, tiv thaiv nws txoj kev khi rau ULK1 thiab kev nrhiav neeg ua haujlwm ntawm FIP200 [107]. Fusion ntawm autophagosomes rau lysosomes yog kho los ntawmRab7 thiab LAMP-2, lysosomal transmembrane protein [120,121]. Tom qab fusion, lysosomalenzymes, feem ntau yog cathepsins, degrade cov ntsiab lus autophagosomal [122].

Nyob rau hauv non-receptor-mediated mitophagy, mitophagy induction txheej txheem activates PTEN-induced kinase 1 (PINK1), uas accumulates ntawm OMM thiab recruits thiab phosphorylates Parkin [123,124]. Parkin accumulates ntawm OMM thiab ubiquitinates OMMproteins, uas ua rau kom muaj zog ntxiv ntawm PINK1 thiab ntau Parkin recruitment [113].

Ntawm cov proteins ubiquitinated los ntawm Parkin yog voltage-dependent anion channels 1 (VDAC1), Mfn1, thiab Mfn2, as Well as TOM20 (translocase ntawm sab nrauv mitochondrial membrane 20), uas tswj mitochondrial fusion.

Ubiquitination ntawm Mfn1/2 yuav thaiv cov txheej txheem thefusion thiab tso cai rau kev sib cais ntawm cov me me thiab puas mitochondria [125].

Cov ubiquitinated proteins nrhiav autophagy adapter proteins, xws li OPTN (optineurin), NBR1 (zeb ze BRCA1), TAX1BP1 (Tax-1 khi protein), NDP52 (nuclear dot protein52), los yog sequestosome-1, uas cuam tshuam. nrog autophagosome proteins xws li GABARAP orLC3 los ntawm LC3 interacting regions (LIR) los kho autophagosome tsim thiab fusion nrog lysosomes [126,127]. Daim duab 2 qhia schematically cov txheej txheem mitophagy.

Daim duab 2. Schematic daim duab ntawm mitophagy. Cov txheej txheem mitophagy induction activates PINK1, uas accumulates ntawm OMM thiab recruits thiab phosphorylates Parkin.

Cov tom kawg ubiquitinatesOMM proteins, xws li mitofusins ​​1 thiab 2 (Mfn), voltage-dependent anion channels 1 (VDAC1), thiab TOM20 (translocase ntawm sab nrauv mitochondrial membrane 20).

Autophagosome tsim pib nrog kev ua kom muaj kev pib ua ntej, muaj ULK1 (Unc-51-zoo li kinase 1), Atg 13 thiab 101 (autophagy-related proteins), thiab FIP200 (focal adhesion kinase family interacting partner 200), thiab txuas ntxiv nrog Kev nrhiav neeg ua haujlwm ntawm chav kawm III phosphatidylinositide 3-kinase (PI3K), beclin1, Atg 14, AMBA1 (autophagy thiab beclin 1 regulator), thiab Vps 34 thiab 15 (vascular protein sorting), uas ua rau tsim cov phosphatidylinositol 3- Phosphate (PI3P).

Cov ubiquitinated proteins recruitautophagy adapter proteins, xws li cov neeg zej zog BRCA1 noob (NBR1), optineurin (OPTN), Tax-1binding protein (TAX1BP1), nuclear dot protein 52 (NDP52), los yog sequestosome-1, uas cuam ​​tshuam nrog autophagosome cov proteins xws li GABARAP lossis LC3 los kho cov kab mob autophagosome. Fusion ntawm autophagosome nrog lysosomes yog kho los ntawm LC3, Rab7, LRRK2, thiab LAMP-2 (saib ntawv).

Txawm li cas los xij, Parkin-kev ywj pheej txoj hauv kev ntawm mitophagy tseem muaj [113], xws li receptor-mediated mitophagy. Cov proteins uas kawm feem ntau koom nrog hauv receptor-mediatedmitophagy yog AMBRA1, FUNDC1 (FUN14 domain-muaj protein ntau 1), NIX (Nip3-}likeprotein), thiab BNIP3, nyob ntawm OMM, nrog rau cardiolipin thiab txwv tsis pub 2 (PHB2). ) ntawm IMM [113].

Cov receptors no tuaj yeem khi rau LC3 hauv Parkin-ywj siab [128] thiab ua rau mitophagy. Lawv cov ntawv sau tuaj yeem qhib tau raws li ntau yam xwm txheej. Forexample, transcription ntawm BNIP3 thiab NIX yog qhib los ntawm hypoxia ntawm hypoxia-induciblefactor 1 alpha (HIF1) [129], uas, tom qab phosphorylation muaj siab affinity rauLC3 [130]. Dephosphorylation ntawm FUNDC1 los ntawm hypoxia pab txhawb nws txoj kev khi rau LC3 [131].

Nyob rau hauv xyoo tas los no, cov kws tshawb fawb tau pom tias mitochondria tuaj yeem raug extruded los ntawm cov cell thiab coj los ntawm endocytosis los yog phagocytosis los ntawm cov hlwb nyob sib ze, qhov twg lawv thaum kawg raug mitophagy, qhov tshwm sim hu ua transcellular mitophagy [113,132].

Nws yog qhov tsim nyog xav tias kev hloov mitochondria rov qab mus rau lub cell soma los ntawm dendrites oraxons yuav ua rau tsis muaj zog, uas yog vim li cas cov neurons tso mitochondria atsynapses kom degraded los ntawm glial hlwb [133].

Nyob rau hauv lem, glial hlwb yuav hloov mitochondria mus rau neurons thiab tiv thaiv tom kawg los ntawm hypoxia thiab nquag tsis ua hauj lwm [134]. Txoj hauv kev zoo rau kev hloov mus rau mitochondrial tseem raug tshawb xyuas, tab sis qee qhov kev tshawb fawb pom tias lub luag haujlwm tseem ceeb rau cov protein txuas mitochondria rau cytoskeletal motor proteins, xws li MIRO1 [135] thaum lwm tus pom kev koom tes ntawm astrocytic GFAP (glial acidicfibrillary protein) thiab neuronal UCP2 (unco protein) ) [136].Lwm txoj kev pov tseg ntawm kev puas tsuaj mitochondria tau raug txheeb xyuas hauv xyoo 1992 [137] thiab hu ua mitoptosis.

Nws ua rau cov hlwb kom degrade mitochondria yam tsis tau qhib MPTP thiab igniting apoptosis [113]. Mitoptosis zoo li yuav qhib los ntawm mitochondrialmembrane depolarization, kev puas tsuaj ntawm mitochondrial DNA (mtDNA), thiab ROS [113].

Cov txheej txheem tseeb ntawm mitoptosis yuav tsum tau kawm ntxiv, tab sis ntau qhov xwm txheej tau piav qhia, xws li o thiab tawg ntawm cristae raws li cytoplasmic extrusionof cristae fragments los ntawm tawg ntawm OMM [138], los yog deterioration ntawm cristae los ntawm coalescence ntawm IMM nrog preservation ntawm intact. [138].

ROS plays lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm autophagy thiab mitophagy. Ib txoj kev, hais los saum no, yog txoj kev mTOR. Ib puag ncig amino acid nplua nuj ua rau kev hloov pauv ntawm mTOR complex 1 (mTORC1) mus rau lysosomal nto, qhov uas nws cuam tshuam nrog Rheband activates mTOR [139], thaum nyob rau hauv kev tshaib plab mTOR colocalizes nrog LC3 thiab pib autophagy [140].

Xav tias mTOR oxidation inhibits nws cov haujlwm, nws muaj feem ntau tiasROS tswj cov kauj ruam no [141]. Tsis tas li ntawd, S-nitrosation ntawm IκB kinase thiab JNK1 los ntawm nitric oxideinhibits lawv cov dej num, uas, nyob rau hauv lem, tiv thaiv mTOR inactivation thiab tso tawm ntawm Beclinfrom lub Beclin-Bcl -2 complex [93,142].

Lwm txoj hauv kev yog beclin-1-chav kawm III PI3K complex, nrog cov cofactors xws li AMBRA1, Bax-interacting factor 1 (Bif-1), lossis Rubicon (RUN domain- thiab cysteine-richdomain-muaj beclin -1-cov protein sib cuam tshuam) [143]. Lwm cov kev tswj hwm ntawm autophagy suav nrog IP3 receptor, AMPK (50-AMP-activated protein kinase), thiab DAPK (tuag-associatedprotein kinase) [144,145].

ROS thiab reactive nitrogen hom induce post-translational protein modifications uas kuj tswj cov kev ua ntawm transcription yam. Piv txwv li, nyob rau hauv Nrf2 (nuclearfactor-erythroid 2-txog yam 2)/Keap1 (Kelch-zoo li enoyl-CoA hydratase-associatedprotein 1) txoj kev, kev hloov kho ntawm Keap1 ua rau kev tso tawm ntawm Nrf2, uas khi rau ARE( antioxidant- teb cov ntsiab lus) thiab translocates mus rau lub nucleus, qhov uas nws activates thetranscription ntawm antioxidant enzymes noob thiab proteins, xws li p62 los yog p53.

Thaum p62activates autophagy [146,147], p5 yog txuas rau ob qho tib si autophagy-inhibiting thiab -promotinggenes los ntawm TIGAR (cov qog protein 53-induced glycolysis thiab apoptosis regulator) thiab DRAM (kev puas tsuaj-tswj autophagy modulator), feem [148,148]

Nyob rau hauv lem, impairedregulation ntawm autophagy ua rau muaj zog oxidative kev nyuaj siab thiab tsub zuj zuj ntawm ubiquitinated proteins, tom kawg ua rau mitochondrial tsis ua hauj lwm thiab ntxiv augmenting ROSgeneration nyob rau hauv ib tug pub-forward voj [93].

4. Lub hlwb thiab Oxidative Stress

Oxygen yog qhov tseem ceeb rau kev ua haujlwm ntawm tes, koom nrog hauv tiam ntawm ATP [61]. Hmoov tsis zoo, vim yog qhov tsis zoo ntawm cov metabolism hauv cov pa oxygen, nrog rau ob leeg electrons ntawm oxygen spinning nyob rau tib lub sijhawm, nws tuaj yeem txais tsuas yog ib lub tshuab hluav taws xob ntawm atime [150], ua rau cov tiam ntawm hom muaj ib qho hluav taws xob tsis sib xws uas tuaj yeem muaj nyob ntawm lawv tus kheej, txhais los ntawm Halliwell li dawb radicals [151].

Cov pa oxygen derivatives yog cov dawb radicals, xws li superoxide anion (•O2−), hydroxyl radical (HO•), hydroperoxylradical (HO2•), thiab peroxyl radicals (ROO•), lossis non-radicals uas tuaj yeem hloov mus rau hauv radicals, xws li Raws li hydrogen peroxide (H2O2) [61,152].

Redox signaling yog siv dav hauv lub hlwb [153], koom nrog hauv cov teeb liab hloov pauv thiab cov noob hloov pauv. Piv txwv li, NADPH oxidases (NOXs) tswj hippocampal mus sij hawm ntev potentiation [154], thiab NOX2- tau txais superoxide thiab hydrogen peroxide tswj hippocampal progenitor cell loj hlob hauv cov neeg laus lub hlwb ntawm phosphatidyl inositol 3 kinase (PI3K) / Akt signaling path [155].

Ib yam li ntawd, NOX-derived H2O2 muaj lub luag haujlwm muaj txiaj ntsig hauv axonal regeneration thiab axonalpathfinding thaum txuas ntawm lub hlwb tsim [156,157]. Raws li qhov tshwm sim ntawm hypoxia, mitochondria-derived superoxide-induced signaling ua rau cov lus teb hloov tau [158].

Txhawm rau tiv thaiv qhov tshwm sim ntawm qhov tshwm sim ntawm cov dawb radicals ntau dhau, cov kab mob lom muaj cov tshuaj tiv thaiv antioxidant, uas tuaj yeem muab faib ua cov enzymaticones (superoxide dismutases, catalase, glutathione peroxidases, glutathione transferases, thioredoxins, thiab peroxiredoxin) thiab tsis-enzymatic tiv thaiv, xws li cov vitamins A, C, E, beta-carotene, los yog glutathione [159].

Thaum twg tus nqi ntawm cov dawb radical ntau ntau tshaj li cov kab mob lom neeg lub peev xwm los ua kom tsis zoo rau lawv, oxidative kev nyuaj siab tshwm sim.

4.1. Vulnerability ntawm lub hlwb rau Oxidative Stress

Lub paj hlwb yog rhiab heev rau oxidative kev nyuaj siab, vim muaj ntau yam laj thawj [153,160-162]:- Kev ua haujlwm muaj peev xwm ua rau calcium nkag thiab nce cov calcium hauv lub cev los ntawm kwv yees li 0.001 µm mus rau roughly 100 µm [ 163] ib.

High intracellularCa2+ activates nNOS (neuronal nitric oxide synthase) thiab ua rau NO (nitric oxide) tsim [164], uas khi rau cytochrome c oxidase thiab inhibits mitochondrialrespiration [165]. Mitochondria sim ua kom tsis txhob muaj cov calcium hauv lub cev, tab sis cov calcium ntau dhau ua rau lub sijhawm qhib MPTP thiab inhibits ATPgeneration, inducing apoptosis [166].

Lub hlwb xav tau lub zog siab heev los tswj cov ionic gradients thiab txhawb kev sib kis ntawm synaptic [19] thiab tso siab rau synaptic mitochondria rau tiam ntawm lub zog xav tau [167]. Piv txwv li, neurotransmitter vesicle tso tawm yuav tsum 1.64 × 105 ATP / s / vesicle [19].

- Lub hlwb muaj cov tshuaj tiv thaiv antioxidant tsawg. Neuronal hlwb muaj 50 npaug tsawg dua catalasethan hepatocytes [168], thaum cytosolic glutathione yog li 50% qis hauv cov neurons piv nrog lwm cov hlwb [153], thiab qhov no yuav txo qis peroxiredoxin kev ua haujlwm [169].- Microglia, lub cev tiv thaiv kab mob ntawm lub hlwb, yog qhib los ntawm H2O2 [170] thiab tsim tawm superoxide ntawm NADPH oxidase isoforms, xav tau rau kev tua kab mob [171].

- Cov metabolism hauv neurotransmitters, xws li dopamine metabolism ntawm monoamineoxidases, generates ROS [153,172].- Neurotransmitters, xws li dopamine, serotonin, los yog adrenaline, tuaj yeem oxidize thiab tsim superoxide [173,174].

- Lub hlwb yog enriched nyob rau hauv redox-active hloov hlau hlau, xws li Cu + los yog Fe2+ [175]. Ironis lub catalyzer nyob rau hauv hydroxyl radical-generating Fenton cov tshuaj tiv thaiv, thiab kuj catalyzesperoxyl thiab alkoxyl radical tiam, yog li pab mus rau ferroptosis, ib tug cell tuag nyob ntawm lipid peroxidation thiab Fe2+ [176]. Cu + yog ib qho kev sib koom ua ke rau Cu / ZnSOD thiab tseem ceeb rau kev taw qhia ntawm tes [177,178] tab sis txhim kho tooj liab-catalyzed Fenton cov tshuaj tiv thaiv [175].

- Lub hlwb tshwj xeeb yog nplua nuj nyob rau hauv cov roj cholesterol, uas yuav ua rau nws pib-oxidation [179] thiab lub hlwb hlwb muaj ntau dua daim nyias nyias saum npoo / cytoplasmic ntim piv, cellular daim nyias nyias yog nplua nuj nyob rau hauv polyunsaturated fatty acids (PUFA), uas yog heev susceptible peroxidation los ntawm dawb. radical nres [153].- Lub hlwb kev loj hlob thiab plasticity cia siab rau cov tsis-coding RNAs (ntev tsis-coding RNAsand microRNAs) [180], tab sis cov molecules no tsis muaj kev tiv thaiv histones thiab yooj yim oxidized [181]. Oxidized messenger RNA ua rau cov nqaij ntuag thiab hloov pauv, ua rau tsis zoo [182].

4.2. Qhov chaw ntawm Dawb radicals

Tshaj dawb radicals tuaj yeem tsim los ntawm ntau qhov chaw.

4.2.1. Mitochondria thiab Oxidative Stress

Mitochondria ib txwm suav tias yog qhov tseem ceeb ntawm ROS. Yam tsawg kawg 10 qhov peev txheej ntawm ROS ntau lawm tau txheeb pom [183] ​​tab sis complexes I (NADH dehydrogenase) thiab III (ubiquinone cytochrome c reductase) ntawm ETC [184] yog qhov tseem ceeb tshaj plaws.

Hloov cov electrons mus rau coenzyme Q los yog ubiquinone los ntawm complexes I thiab II ua rau inubiquinol (txo ubiquinone, QH2), uas yuav regenerate coenzyme Q ntawm semiquinone anion (•Q−), ib tug tsis ruaj tsis khov intermediate uas yuav hloov electrons rau molecular oxygen, ua rau superoxide tsim. [60]. Ua cov tshuaj tiv thaiv uas tsis yog-enzymatic, ntau dua metabolicrates ua rau muaj zog superoxide ntau lawm [185].

Superoxide tsis ruaj khov thiab hloov pauv los ntawm mitochondrial superoxide dismutase 2 (SOD2, manganese SOD) thiab cytosolic SOD1 (tooj liab-zinc SOD) rau hauv cov hydrogen peroxide (H2O2).

Lub tom kawg tuaj yeem tawm ntawm IMM los ntawm cov kab aquaporin thiab nthuav tawm los ntawm OMMinto lub cytoplasm, qhov chaw uas nws ua haujlwm rau redox signaling, los yog ntxiv txo rau dej bycatalase, glutathione peroxidases, thiab peroxiredoxins [186–189]. Lwm yam mitochondrial Cheebtsam uas ua rau ROS tsim muaj xws li monoamine oxidase, glycerol phosphatedehydrogenase, -ketoglutarate dehydrogenase, thiab p66shc [60,183,190].

Mitochondrial ROS ntau lawm yog ua raws li kev hloov pauv los ntawm cov txheej txheem metabolic.Piv txwv li, NADH / NAD + piv cuam tshuam cuam tshuam rau tus nqi ntawm ROS tiam, uas nce ntau tshaj linearly nrog NADH txo [191]. Cov qib succinate tuaj yeem hloov pauv txawm tias nyob rau hauv ib txwm muaj ntawm 0.3 thiab 1 mM [192], nrog rau kev nce succinate concentrations ua rau mitochondrial ROS tiam [183,193].

Tus nqi ntawm ROS ntau lawm kuj cuam tshuam los ntawm mitochondrial membrane peev xwm [183]. Active mitochondrial phosphorylation ntawm ADP los yog mitochondrial calcium uptake txo cov membrane muaj peev xwm, uas cuam tshuam rau redox peev xwm ntawm ETC thiab txo ROS ntau lawm [194]. Oxygen deprivation los yog ischemia ho nce mitochondrial ROS tiam [195], txawm hais tias cov nyhuv no yuav tsis raug ntaus nqi rau mitochondria ib se, tab sis theej rau cov teeb liab txoj kev tshwm sim los ntawm hypoxia [196].

4.2.2. NADPH Oxidase ua qhov chaw ntawm ROS

NADPH oxidase (NOX) tau piav qhia thawj zaug hauv phagocytes [197], tom qab uas xyaNOX noob tau txheeb xyuas: NOX 1–5 thiab DUOX 1 thiab 2 [198]. Lub hlwb nthuav tawm feem ntau yog NOX2, nrog rau NOX4, ob qho tib si tau piav qhia hauv cortex thiab CA1 hippocampalareas [199].

NOX2 enzyme complex muaj ib daim nyias nyias cytochrome b558, ntau cytosolic proteins, thiab Rac G-protein. Tom qab phosphorylation ntawm cytosolicproteins thiab ua kom cov Rac, cov enzyme hloov mus rau daim nyias nyias thiab tsim activeNOX2 nrog cytochrome b558 [200]. Tsis tas li ntawd, NOX2 hloov cov protons hla lub membrane thiab ua rau superoxide tiam [198].

NOX4 feem ntau yog H2O2, siv los ua tus xa xov thib ob rau kev loj hlob ntawm tes thiab kev sib txawv [201].

NOX tau piav qhia hauv cov neurons, astrocytes, thiab microglia [202], thaum nyob rau theem cellular, NOX isoforms nyob rau hauv cov endoplasmic reticulum, nucleus, plasma membrane, thiab mitochondria [203,204]. Lub ROSgenerated los ntawm activated NOX tuaj yeem depolarize lub mitochondrial membrane thiab, nrog rau calcium, tuaj yeem ua rau qhib MPTP [205] nrog rau qhib phospholipase C nrog cov kev hloov pauv hauv daim nyias nyias [198].

4.2.3. Monoamine Oxidase ua qhov chaw ntawm ROS

Cov monoamine oxidases (MAO A thiab B) yog flavoenzymes nyob rau ntawm OMM uas catabolize amine neurotransmitters, xws li serotonin, epinephrine, thiab dopamine [206].

MAO-A yog qhia hauv neurons, thaum MAO A thiab B tuaj yeem pom hauv glial hlwb [198]. Lawv siv FAD los rhuav tshem cov monoamines, cov txheej txheem thaum lub sij hawm aldehydes raug tsim, thaum H2O2 tshwm sim los ntawm FAD-FADH2 voj voog [198].

4.2.4 ib. Peroxisomes thiab ROS Production

Txawm hais tias cov txheej txheem metabolic peroxisomal tseem ceeb ua rau H2O2 tiam yog -oxidation ntawm cov roj fatty acids dawb [60], ob peb lwm cov peroxisomal enzymes, xws li xanthineoxidase, D-aspartate oxidase, acyl CoA oxidases, D-amino acid oxidase, urate oxidase, los yog L. - -hydroxy oxidase, tuaj yeem tsim ntau yam ROS, xws li superoxide, hydrogenperoxide, nitric oxide, lossis hydroxyl radicals [207].

4.2.5 ib. Exogenous Sources ntawm ROS

Ntxiv nrog rau ntau qhov chaw ntawm endogenous ROS, exogenous ROS tuaj yeem ua rau muaj kev ntxhov siab oxidative. Cov khoom siv ntau tshaj plaws yog dej thiab huab cua muaj kuab paug, ultraviolet lightexposure, cawv thiab haus luam yeeb, tshuaj tua kab, muaj kuab tshuaj, noj tsis noj qab haus huv (withsmoked nqaij, high-rog noj), raug rau hnyav hlau los yog hloov hlau (Fe, Cr, Co, Cu. , Hg, Pb, As), nrog rau qee yam tshuaj, xws li Doxorubicin, Bleomycin, Metronidazole, oreven Paracetamol [60].

4.3. Cov hom phiaj ntawm ROS

Cov reactive dawb radicals heev ua rau cov proteins, lipids, thiab nucleic acids [152].

4.3.1. Proteins thiab ROS

Proteins tuaj yeem oxidized los ntawm radicals, xws li superoxide, hydroxyl radical, peroxyl, hydrooperoxyl, los yog alkoxyl radicals, nrog rau cov hom tsis-radical lossis singlet oxygen [208].

Oxidation ntawm cov amino acids xws li lysine, arginine, proline, los yog threonine ua rau carbonylderivatives, siv los ua cov cim ntawm oxidative kev nyuaj siab [209]. Methionine thiab cysteine ​​​​, raws li sulfur-muaj cov amino acids, yog heev raug rau oxidation, ua rau disulfides thiab methionine sulphoxide [210].

Protein oxidation ua rau cov protein-protein cross-linkages, hloov kev ua haujlwm, tsis ua haujlwm enzymatic, thiab kev hloov pauv ntawm cov receptor thiab thauj cov protein [211].

Ntxiv mus, hydrogen peroxide thiab hydroxyl radicals inhibitglutamate uptake los ntawm astrocytes, augmenting excitotoxicity [212]. Raws li qhov tshwm sim, cov proteins uas hloov pauv no yuav tsum raug tshem tawm, los ntawm txoj kev autophagy-lysosome lossis los ntawm theubiquitin-proteasome system [213,214].

Lub ubiquitin-proteasomal system (UPS), lub ntsiab degradation txoj kev ntawm ubiquitinated misfolded proteins thiab luv-lived signalingmolecules, muaj ib tug 19S subunit thiab ib tug catalytically active 20S core [215]. Cov txheej txheem tswj hwm nrog chaperone proteins nthuav tawm lub hom phiaj protein, tshem tawm cov cim npe ubiquitin hauv cov txheej txheem anATP-nyob, tom qab ntawd cov phiaj xwm protein tau nkag mus rau hauv cov tub ntxhais catalytic thiab degraded los ntawm cov enzymes proteasomal.

Raws li kev ntxhov siab hnyav, UPS tau dhau mus, thiab txoj kev autophagy-lysosome tau them nyiaj rau cov protein ntau puas tsuaj [107] .A series ntawm autophagy receptors, xws li p62, NDP52, lossis NBR1 paub txog ubiquitinmoiety thiab lub hom phiaj tagged proteins rau autophagosome los ntawm kev khi rau Atg8/LC3 [216,217].

FOXO3 (forkhead box O3) yog ib qho kev hloov pauv hloov pauv los ntawm oxidative kev nyuaj siab, uas tswj cov kev hloov pauv ntawm cov noob koom nrog hauv proteasomal thiab autophagic protein degradation [218]. Tsis tas li ntawd, Parkin, ubiquitin ligases, thiab CHIP (C-terminus ntawm Hsc70-kev cuam tshuam cov protein) ua rau ob qho tib si proteasomal thiab autophagosomal degradation ntawm cov protein [107,219].

Cov qib txheeb ze ntawm BAG (Bcl-2 txuam transgene) 1 thiab BAG3, co-chaperone proteins, coj cov cellular protein degradation txoj kev mus rau cov proteasomal los yog phagosomal ib [220].

4.3.2. Lipids thiab ROS

Dawb radicals los yog hom tsis-radical oxidative tua CC ob daim ntawv cog lus ntawm lipids, uas yog vim li cas polyunsaturated fatty acids yog heev yooj yim rau oxidative nres [221].

Nyob rau theem pib, cov dawb radical cuam tshuam nrog pawg methylene hauv fatty acid thiab tsim cov lipid radical los ntawm dissociating hydrogen atom [222]. Tsis tas li ntawd, cov lipid radicalsreact nrog molecular O2 los tsim peroxyl radicals (ROO•) [223], uas pib muaj kev sib txuas ntawm tus kheej-txhim kho cov tshuaj tiv thaiv ua kom cov txheej txheem.

Qhov no ua rau cyclic peroxides thiab hydrooperoxides, uas tuaj yeem degraded ntxiv rau aldehydes, cov khoom kawg yogmalondialdehyde (MDA), hydroxynonenal (HNE), thiab acrolein [224].

Cov txheej txheem sterminated los ntawm kev sib cuam tshuam ntawm lipid radicals nrog lipid peroxides, ua rau cov tsiaj tsis muaj zog [221], los yog los ntawm kev cuam tshuam ntawm endogenous lossis exogenousantioxidants (vitamin C thiab E) [222,225].

Hauv qhov tsis tshua muaj siab, 4-HNE ua lub luag haujlwm tseem ceeb hauv homeostatic los ntawm kev ua lub cim qhia molecule thiab modulating noob qhia los ntawm inducing post-translational proteinmodifications.

Lub hom phiaj feem ntau yog thiol residues [225]. Los ntawm kev cuam tshuam nrog cysteine ​​thiols hauv Keap1, 4-HNE ua rau kev tso tawm Nrf2, uas tom qab translocating rau lub nucleus qhib qhov kev qhia ntawm ARE noob xws li glutathione-S-transferase, NADPH-dependent quinone reductase, lossis heme oxygenase{ {7}} [226]. Lwm lub hom phiaj ntawm 4-HNEis NF-κB, ib qho kev hloov pauv rau cov cytokines pro-inflammatory, ib txwm tswj tau zoo los ntawm kev khi rau IκB (inhibitor kappa B).

Raws li kev ntxhov siab ntawm tes, IκB kinase phosphorylates IκB txhawb kev tso tawm ntawm NF-κB, ib qho kev hloov pauv uas cuam tshuam qhov kev hloov pauv ntawm antiapoptotic Bcl -2 cov protein thiab inflammatory cytokines, xws li interleukin -6 (IL-6) .

4-HNE inhibits IκB kinase, yog li tiv thaiv IκB phosphorylation thiab NF-κB nuclear translocation [227].Txawm li cas los xij, raws li qhov tshwm sim ntawm daim nyias nyias lipid peroxidation, daim nyias nyias altersits permeability, tsub kom nws rigidity, thiab tej zaum yuav txawm poob siab [228] .

Tsis tas li ntawd, lipid peroxidation cov khoom tau koom nrog hauv txoj hauv kev ua kom pom tseeb. Intracellularaccumulation ntawm 4-HNE tuaj yeem ua rau apoptosis los ntawm ob qho tib si sab hauv thiab sab nrauv [225]. 4-HNE nce qhov kev qhia ntawm p53, ua raws li kev ua kom p21, JNK, Bax, thiab caspase 3 [229], ua rau caspase-mediated apoptosis.

Tsis tas li ntawd, 4-HNEinitiates txoj kev khi ntawm cov protein uas cuam tshuam nrog kev tuag Daxx mus rau sab hauv lub cev ntawm Fas [230], yog li tau koom nrog hauv kev hloov kho ntawm txoj kev extrinsic ntawm apoptosis los ntawm cov kab hluav taws xob qis qis ASK1 thiab JNK [225].

Ntxiv mus, cov qib siab ntawm HNE tuaj yeem tsim kev sib txuas nrog JNK, lub luag haujlwm rau kev hloov kho histone thiab ua kom yooj yim rau kev hloov pauv hauv nuclear [231], lossis tuaj yeem qhib JNK los ntawm SPKK1 (kev ntxhov siab-activated proteinkinase kinase-1) ua kom [232]. Ib yam li ntawd, HNE tuaj yeem qhib ERK los ntawm kev ua kom MEK1/2 thiab p38MAPK (mitogen-activated protein kinase) [233,234].

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