Reappraisal Of Metabolic Dysfunction in Neurodegeneration: Focus On Mitochondrial Function Thiab Calcium Signaling Part 7
Aug 30, 2024
Peroxisomal lipid metabolism
Metabolic dysregulation cuam tshuam nrog peroxisome dysfunction tuaj yeem ua rau kev txhim kho ntawm NDDs.
Oxisomes, tseem hu ua oxidosomes los yog catalase, yog tshwj xeeb subcellular organelles nyob rau hauv cov hlwb uas siv tau oxygen los hloov oxides rau hauv dej thiab oxygen. Exosomes ua si lub luag haujlwm tseem ceeb hauv metabolic thiab tiv thaiv hauv ntau yam kab mob thiab tseem muaj feem xyuam nrog ntau cov txheej txheem physiological.
Kev tshawb fawb nyob rau hauv xyoo tas los no tau qhia tias kev sib raug zoo ntawm exosomes thiab nco kuj tau txais kev saib xyuas ntxiv. Qee qhov kev tshawb fawb tau pom tias qhov kev faib tawm thiab kev ua haujlwm ntawm exosomes hauv lub hlwb muaj feem cuam tshuam nrog cov txheej txheem kev txawj ntse. Tshwj xeeb, exosomes tuaj yeem tshem tawm cov teeb meem xws li dawb radicals thiab peroxides hauv cov hlwb, yog li tiv thaiv kev ruaj ntseg thiab kev ua haujlwm ntawm neurons.
Tsis tas li ntawd, ntau qhov stimuli sab nraud thiab sab hauv lub xeev txawv txav tuaj yeem cuam tshuam rau tus lej thiab kev ua haujlwm ntawm exosomes, yog li cuam tshuam rau lub peev xwm nco. Piv txwv li, ntev mus rau ib puag ncig muaj kuab paug, hluav taws xob, thiab tsis muaj oxygen tuaj yeem txo qis ntawm exosomes, nce dawb radicals thiab oxidative puas tsuaj, thiab tom qab ntawd ua rau kev noj qab haus huv thiab cov teeb liab hloov ntawm cov neurons, thaum kawg ua rau kev nco tsis zoo thiab kev txawj ntse poob. .
Ntawm qhov tsis sib xws, kev tawm dag zog kom zoo, noj zaub mov, kho lub siab lub ntsws, thiab cov pa oxygen txaus tuaj yeem txhawb txoj kev loj hlob thiab kev ua haujlwm ntawm exosomes, yog li txhim kho cov metabolic thiab teeb liab transduction efficiency ntawm neurons, thiab txhim kho kev nco muaj peev xwm thiab kev txawj ntse. Tsis tas li ntawd, cov kev tshawb fawb kuj tau pom tias qee cov khoom siv ntuj tsim thiab tshuaj, xws li vasopressin thiab qee yam khoom noj qab haus huv, kuj tuaj yeem txhawb txoj kev loj hlob thiab kev ua haujlwm ntawm oxidases, yog li txhim kho kev nco thiab kev txawj ntse.
Hauv cov ntsiab lus, muaj kev sib raug zoo ntawm oxidases thiab nco. Nyob rau hauv lub neej niaj hnub, peb yuav tsum tau xyuam xim rau kev tiv thaiv thiab txhawb cov qib thiab kev ua ntawm oxidases, txais yuav ib tug noj qab nyob zoo txoj kev ua neej, thiab tsim nyog tshuaj cuam tshuam los txhim kho kev nco thiab kev txawj ntse muaj nuj nqi. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob yam, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.
Nyem Paub txhawm rau txhim kho lub cim xeeb luv luv
Peroxisomes yog cov muaj zog heev thiab tseem ceeb metabolicorganelles uas tuaj yeem sib txuas lus ncaj qha nrog mitochondria thiab pab txhawb cov cellular lipid metabolism, xws li cov oxidation ntawm cov kab mob ntev-ntev fatty acids (VLCFAs), synthesis ntawm phospholipids, xws li plasmalogen / ether lipids (myelin sheath lipids) thiab docosahexaenoic acid (DHA), thiab cov kev cai ntawm redox thiab inflammatory signaling.
Tsis tas li ntawd, lub paj hlwb yog cov khoom siv lipid-nplua nuj, thiab myelinsheaths yog nplua nuj nyob rau hauv plasmalogens / ether lipids synthesizedin peroxisomes. Yog li, kev hloov pauv me ntsis hauv peroxisomal lipid metabolism tuaj yeem sawv cev rau cov txheej txheem tseem ceeb uas ua rau muaj kev hloov pauv hauv kev ua haujlwm neuronal (saib hauv [401]).
Hauv AD, kev hloov pauv hauv lipid homeostasis / peroxisomefunction suav nrog txo qis ntawm plasmalogens thiab DHA thiab nce qib ntawm VLCFA. Cov kev hloov pauv ntawm cov kev hloov no cuam tshuam nrog kev loj hlob ntawm tus kab mob [402, 403] thiab tau pom tias muaj kev hloov pauv ntawm cov cell membrane thiab nce qib hauv cov roj cholesterol.
Cov kev hloov no nce -secretaseand -secretase kev ua ub no, ua rau muaj kev txhim kho A tiam, tau hyperphosphorylation, synaptic dysfunction, thiab neuroinflammation [404, 405].
Tsis tas li ntawd, peroxisomal -oxidation inhibition nce A tiam inrat hlwb (saib xyuas hauv [405]). Ib yam li ntawd, kev hloov pauv loj hauv lipid muaj pes tsawg leeg (txo hauv DHA thiab plasmalogens) ntawm frontal cortex lipid rafts los ntawm PD cov neeg mob tau tshaj tawm [406]. Kev txo qis hauv ether lipids txo qisCa2+- nyob ntawm qhov tso tawm neurotransmitter thiab lub peev xwm ua pa ntawm synaptic mitochondria [407].
Yog li, qhov txo qis ntawm ether lipids hauv mitochondrial daim nyias nyias yuav cuam tshuam OxPhos complexes thiab yog li ATP tiam txaus los cuam tshuam cov neurotransmission.
Txawm li cas los xij, tag nrho lub luag haujlwm ntawm peroxisomallipid metabolism hauv NDDs tau piav qhia tsis zoo. Cov kev tshawb fawb ntxiv yuav tsum tau txiav txim siab seb puas yog peroxisomallipid dysfunction ncaj qha cuam tshuam rau kab mob etiology lossis yog qhov tshwm sim thib ob. Peb xa tus nyeem ntawv mus rau lwm qhov kev tshuaj xyuas tsis ntev los no rau cov ncauj lus kom ntxaws txog cov metabolism hauv lipid peroxisomal hauv NDDs thiab nws cov metaboliccooperation nrog mitochondria [405, 408].
Modulation ntawm mitochondrial muaj nuj nqi raws li lub hom phiaj kho mob rau neurodegeneration Raws li tau tham ua ntej lawm, dysregulation nyob rau hauv mCa2+ homeostasismight yog ib qho kev tshwm sim nyob rau hauv uas ua rau mitochondrial dysfunction nyob rau hauv NDDs.
Vim li no, ntau yam kev sib txuas ntawm cov khoom siv sib xyaw ua ke txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm Cov tswv yim kho tau zoo, tau sau tseg hauv Table 1, suav nrog txo mCa2+ uptake, txhim kho mCa2+ reflux, thiab khaws cia mitochondrialarchitecture/functions (xws li kev sib dhos ntawm cov kab mob ua pa thiab ATP synthase), bioenergetics, axonal thauj ntawm mitochondria, thiab mitochondrialproteostasis.
Txawm li cas los xij, nws tseem tsis tau paub meej tias qhov nce mCa2+ reflux lossis txo mitochondrial mCa2+uptake yuav zoo dua rau kev tiv thaiv kab mob. Ob leeg txaus los txwv mCa2+ overload thiab kho mCa2+ dysregulation.
Tseem, ob peb lub ntsiab lus yuav tsum tau ua tib zoo xav, xws li yog cov modulators ntawm mitochondrial mCa2+ homeostasis yuav cuam tshuam tsis zoo rau Ca2+-nyob ntawm lub cev muaj zog, xws li TCA cycle flux thiab mitochondrialdynamics.
Nws tseem yuav tsum tau muab sau tseg tias txawv NDDsmight muaj kab mob tshwj xeeb kev cai ntawm mtCU channel kev ua, uas yuav tsum tau muaj kev sim ntau ntxiv. Ntxiv rau qhov no, cellular heterogeneity hauv mitochondrialfunction kuj yuav tsum tau txiav txim siab; Piv txwv li, axonaland synaptic mitochondria tau tshaj tawm tias tau koom nrog Ca2+ buffering thiab presynaptic kis tau tus mob, whereas lub soma yog thawj qhov chaw rau mitochondrial qualitycontrol.
Yog li ntawd, kev nkag siab zoo thiab kev tswj hwm ntawm MCU, lossis kev sib xyaw ntawm cov khoom siv sib xyaw ua ke uas ua rau kom mCa2+ tsis muaj peev xwm thiab tseem muaj zog tuaj yeem tsim nyog los tswj kev sib kis tau zoo thiab kho NDDs zoo.
Cov kev sib tw, cov lus xaus, thiab cov kev tshawb fawb yav tom ntej
Kev nkag siab ntau ntxiv thiab tsis txaus ntseeg ntawm cov cellular thiab molecular mechanisms hloov pauv neuronal mitochondrial metabolism hauv NDDs tseem xav tau. Ntau cov lus nug tseem ceeb yuav tsum tau teb, xws li (1) Yuav ua li cas mitochondrial tsis xws luag yog qhov tseem ceeb nyob rau hauv ntau yam NDDs nrog ntau yam etiologies thiab pathologies?
(3) Puas yog metabolic defects ua rau neurodegeneration, los yog puas neuronal dysfunction ua inmetabolic defects? (4) Dab tsi yog cellular thiab molecular txheej xwm uas pib mitochondrial dysfunction hauv neurodegeneration?
(5) Yuav ua li cas cov neurons paub txog bioenergeticcrisis thaum muaj kev ntxhov siab lossis hauv cov kab mob pathology? (6) Yuav ua li cas cell-specific metabolic profiles cuam tshuam cellular crosstalk nyob rau hauv cov ntsiab lus ntawm cov kab mob? 8) Cov kev taw qhia txog dej ntws thiab nqes dej twg muaj feem cuam tshuam rau lub sijhawm muaj teeb meem bioenergetic hauv NDDs sib txawv? 9) Dab tsi yog cov qauv zoo tshaj plaws los txiav txim siab cov xwm txheej no rau kev txhais lus rau tib neeg?Ntawm no peb tau sau tseg tias ntau cov xov tooj ntawm tes uas raug cuam tshuam thaum lub sij hawm neurodegeneration tag nrho yuav tsum muaj qib siab ntawm ATP (xws li, postsynaptic signaling, axonal thauj, protein clearance mechanisms, andneurotransmission).
Peb kuj tau tshuaj xyuas cov pov thawj uas txhawb qhov kev xav tias mCa2+ thiab metabolic impairments yog thawj cellular defects hauv NDD pathogenesis. Interestingly, tag nrho cov NDDs sib koom cov txheej txheem ntawm cov kab mob pathology thiab mitochondrial defects yuav ua rau lub hauv paus mechanism hauv NDD kev loj hlob.
Txawm li cas los xij, nws tseem ceeb npaum li cas mitochondrial dysfunction cuam tshuam ncaj qha rau cov protein sib sau ua ke thiab lub hlwb thaj tsam thiab cov xov tooj ntawm tes tshwj xeeb tsis ua haujlwm hauv NDDs thiab seb mitochondrial dysfunction yog qhov ua rau lossis qhov tshwm sim ntawm cov kab mob hauv qab no.
Ntawm no, peb tawm tswv yim tawm tswv yim zoo ntawm mitochondrial defects thiab kab mob pathology uas piav qhia ntau yam txheej txheem ntawm NDDs. Nws yog qhov tseeb tias thaum ntxov mitochondrial dysfunction cuam tshuam ncaj qha rau cov protein sib sau los ntawm ATP-dependent proteostasis machinery (protein synthesis, folding, and degradation) ua ke nrog oxidative stressand o thiab txhawb nqa cell-type-specific lossdue rau mitochondrial tuag signaling los yog vim metabolic.
Cov ntawv ceeb toom tsis ntev los no qhia tias kev sib sau ua ke ntawm cov protein ntau xa mus rau mitochondria thiab mitochondrial protein zoo tswj yuav txo tau cov protein sib sau ua ke.
Mitochondrial dysfunction ua rau tsis ua hauj lwm ntawm mitochondrial proteostasis tuaj yeem yog lwm qhov tseem ceeb rau pathology-specific protein aggregation.Rau cov ncauj lus kom ntxaws uas mitochondrial dysfunction ua rau protein aggregation, peb xa mus rau cov neeg nyeem rau lwm cov kev tshuaj xyuas tsis ntev los no [409, 410].
Ib hom xovtooj ntawm tes/brainregion-kev cai tshwj xeeb ntawm mitochondrial functionand mCa2+ signaling tsis muaj thiab yuav ua li cas qhov no contributes rau txawv kab mob pathologies yog unexplored nkaus.
Ua tiav kev nkag siab thiab kev tswj xyuas meej ntawm mtCUfunction hauv NDDs sib txawv tuaj yeem pab txhais cov txheej txheem hauv cov ntaub so ntswg- thiab cov xov tooj ntawm tes tshwj xeeb NDDs.
Lwm qhov kev sib tw loj hauv NDD kev tshawb fawb yog xaiv cov qauv kev sim uas rov hais dua cov kab mob ntawm tib neeg cov kab mob. Tau ntau xyoo lawm, tus qauv tsiaj txhu yog qhov tseem ceeb vim tias lawv muaj peev xwm rov hais dua tib neeg kev hloov pauv caj ces thiab ua raws li kev kho mob tseem ceeb.
Cov qauv qauv no tau muab kev nkag mus rau kev txheeb xyuas hauv vivo systemic kev sib cuam tshuam thiab kawm txog kev loj hlob, metabolic, thiab kev coj cwj pwm tshwm sim, uas tsis muaj peev xwm ua tau hauv cov xov tooj ntawm tes lossis cov neeg mob.
Arguably, kev tshawb pom hauv cov qauv tsiaj tau ua rau kev nkag siab zoo dua ntawm cov txheej txheem molecular ntawm cov kab mob pathogenesis tab sis ua tsis tiav los txhais lus rau tib neeg.
Txawm li cas los xij, qhov tsis ua tiav los txhais cov kev nkag siab tau txais los ntawm cov qauv nas rau hauv tib neeg tsis yog ib txwm yog vim qhov tsis zoo ntawm tus tsiaj qauv ib se. Piv txwv li, ntau ntawm cov kev tshawb fawb no tsis muaj cov ncauj lus kom ntxaws txog kev sim ua rau muaj kev cuam tshuam thiab tsis suav nrog lwm yam sib txawv.
Lwm txoj hauv kev siv tau uas tuaj yeem pab rov qab kho tib neeg cov kab mob xws li kev tshawb fawb ntawm postmortem tib neeg lub hlwb thiab tib neeg iPSCs, thiab organoids yuav pab tau raws li kev txhais lus stepping stonesto kho.
Lub hlwb postmortem tib neeg lub hlwb yog tshwj xeeb yog pab tau nyob rau hauv quantifying cellular thiab molecular cim kab mob thiab cov pathology ntawm neural dab. Txawm li cas los xij, kev nkag mus rau cov qauv no tsuas yog txwv, thiab qhov zoo ntawm cov ntaub so ntswg cuam tshuam los ntawm tus neeg mob tus mob post-mortem, postmortem interval, sau lub sij hawm, thiab kev saib xyuas txhua yam uas tuaj yeem qhia txog qhov txawv txav.
Tib neeg iPSCs yog ntau yam cuab yeej los ua qauv humanneurons thiab tsim nyog rau tib neeg hauv vitro kev tshawb fawb, xws li kev tshuaj ntsuam xyuas tshuaj ntau dhau. Txawm li cas los xij, lawv tsis tuaj yeem ua rau hauv vivo cellular physiology uas coj mus rau hauv tus accountorgan thiab cellular crosstalk thiab complex milieuof tag nrho cov kab mob.
Peb ntseeg tias muaj ntau hom qauv, suav nrog cov qauv tsiaj muaj zog thiab peb-dimensional cellular systems, yuav pab tau zoo dua txhais cov kab mob ntawm NDDs thiab pab kom muaj kev ntsuam xyuas ntau dua ntawm cov tshuaj thiab kev kho mob rau kev txhais lus kho mob.
Tseeb tiag, nws yog ib qho tseem ceeb los tsim cov qauv tsiaj uas muaj zog uas phenocopyeither cov tsev neeg lossis cov tsev neeg tsis muaj tsev neeg ntawm cov kab mob no.
Ib qho kev nce hauv kev sim tsim kom zoo siv cov qauv tsim tsiaj uas muaj zog uas rov ua dua qhov nyuaj ntawm tag nrho lub paj hlwb, suav nrog kev ua tiav tag nrho ntawm cov neuronal circuits, glial complexity, thiab cov vascular thiab immunologic Cheebtsam, yuav muab kev nkag siab zoo txog yuav ua li cas mitochondrial metabolism cuam tshuam cov kab mob pathogenesis.
Hauv kev xaus, kev nkag siab zoo ntawm kev tswj hwm cov metabolism, kev txheeb xyuas cov hom phiaj ntawm mitochondrial (saib Table 1), thiab kev txiav txim siab ntawm qhov kev txiav txim ntawm lub cev ntawm cov kab mob hauv lub cev yog qhov tseem ceeb tshaj plaws rau kev txhim kho cov hom phiaj kho tshiab los tawm tsam NDDs.
Cov ntawv luv
NDDs: Cov kab mob neurodegenerative; AD: Alzheimer's disease; PD: Parkinson tus kab mob; HD: Huntington tus kab mob; PET: Positron emission tomography; A: Amyloid-beta; NFTs: Neurofbrillary tangles; OxPhos: Oxidative phosphorylation; ETC: Electron thauj saw; PDH: Pyruvate dehydrogenase; -KGDH: Alpha-ketoglutarate dehydrogenase; ICDH: Isocitrate dehydrogenase; SDH: Succinate dehydrogenase; MDH: Malate dehydrogenase; Δψm: Mitochondrial membrane muaj peev xwm; COX: Cytochrome-c-oxidase; iCa2+: Intracellularcalcium; mtCU: Mitochondrial calcium uniporter channel; mCa2+: Mitochondria calcium; NCLX: Mitochondrial Na+/Ca2+ exchanger; MCU: Mitochondrialcalcium uniporter; mPTP: Mitochondrial permeability hloov pore; PMCA: Plasma membrane Ca2+ ATPase; NCX: Na+/Ca2+ exchanger; TRP: Lub peev xwm transientreceptor; VDCC: Voltage-gated calcium channels; AMPAR: -Amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; mGluR: Metabotropicglutamate receptors; NMDAR: N-Methyl-D-aspartate receptor; NCX: Na+/Ca2+ exchanger; SOCE: khaws cia cov calcium nkag; IP3R: Inositol 1,4, 5-trisphosphate receptor; RYR: Ryanodine receptor; SERCA: Sarco/endoplasmicreticulum Ca2+-ATPase; TCA: Tricarboxylic acid voj voog; MAMs: Mitochondrialassociated membranes; ROS: Reactive oxygen hom; RNS: Reactive nitrogen hom; AMPK: AMP-activated protein kinase; PGC-1 : Peroxisome proliferatoractivated receptor (PPAR)- co-activator 1 ; mtDNA: Mitochondria DNA.
Kev lees paub
Txoj haujlwm no tau txais kev txhawb nqa los ntawm NIHR01HL136954, R01HL142271, P01HL147841, thiab P01HL134608 rau JWE, NIH K99AG065445 rau PJ, thiab NIH F32HL151146 rau JFG
Cov sau phau ntawv pab
PJ thiab JFG tau sau cov ntawv sau, thiab PJ tsim thiab tsim cov duab. JWE tau txais kev tshuaj xyuas thiab sau thiab kho cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo cov ntawv sau kawg.
Kev tsis sib haum xeeb
Cov kws sau ntawv tshaj tawm tias qhov kev tshawb fawb tau ua thaum tsis muaj kev lag luam lossis kev sib raug zoo nyiaj txiag uas tuaj yeem txhais tau tias muaj kev cuam tshuam ntawm kev txaus siab.
Cov ntaub ntawv
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