Predicting Mitochondrial Dynamic Behavior nyob rau hauv Genetically Defined Neurodegenerative Diseases Part 3
Jul 25, 2024
Mitochondria tsis yog qhov txawv txav ntawm txhua yam kab mob hauv cov kab mob genetic neurodegenerative, thiab mitochondrial dysdynamism tsis tas yuav yog ib feem ntawm tag nrho cov kab mob neurodegenerative uas nthuav tawm mitochondrial abnormalities.
Mitochondria yog ib qho khoom nruab nrog hauv cov hlwb uas yog lub luag haujlwm rau kev tsim hluav taws xob thiab cov metabolism hauv cov cell. Nyob rau hauv xyoo tas los no, kev tshawb fawb tau pom tias mitochondrial abnormalities yuav muaj feem xyuam rau kev nco. Txawm li cas los xij, peb yuav tsum tsis txhob txhawj xeeb txog qhov tsis zoo ntawm mitochondrial abnormalities, vim hais tias niaj hnub science thiab technology tau dhau los ua ntau dua, thiab peb tuaj yeem tiv thaiv qhov tshwm sim ntawm mitochondrial abnormalities los ntawm ntau txoj kev thiab cov khoom noj qab haus huv hauv lub neej.
Ib txoj kev tshawb nrhiav pom tias mitochondrial abnormalities tuaj yeem cuam tshuam nrog kev nco tsis tau hauv cov neeg laus. Qhov no yog vim qhov kev puas tsuaj ntawm mitochondrial tuaj yeem ua rau muaj kev puas tsuaj rau neuronal thiab kev tuag ntawm tes, yog li cuam tshuam rau kev ua haujlwm ntawm lub hlwb neurons thiab ua rau kev nco thiab kev paub tsis meej. Txawm li cas los xij, qhov no tsis tau txhais hais tias mitochondrial abnormalities yog lub hauv paus ua rau nco tsis tau, vim hais tias kev nco tsis tuaj yeem tshwm sim los ntawm lwm yam, xws li kev noj zaub mov tsis zoo, lub hlwb puas, kev laus, thiab lwm yam.
Txhawm rau tiv thaiv mitochondrial abnormalities, peb tuaj yeem txhim kho peb txoj kev noj qab haus huv los ntawm kev hloov peb txoj kev ua neej thiab kev noj haus. Piv txwv li, kev tawm dag zog txhua hnub thiab kev tawm dag zog kom zoo tuaj yeem txhawb kev tsim ntawm mitochondria, txhim kho lub cev metabolic qib, tswj lub cev kev noj qab haus huv, thiab txhim kho kev nco. Tsis tas li ntawd, kev noj haus kuj yog ib qho tseem ceeb. Peb yuav tsum noj zaub mov tsis tu ncua, noj zaub mov kom zoo xws li txiv hmab txiv ntoo, zaub, thiab nplej, thiab ua tib zoo saib xyuas kom tsis txhob muaj suab thaj thiab cov zaub mov muaj roj ntau.
Tsis tas li ntawd, cov tshuaj tiv thaiv tuaj yeem siv los tiv thaiv mitochondria nyob rau hauv kev sib haum xeeb. Muaj twb muaj qee cov tshuaj tsom rau mitochondria ntawm kev ua lag luam, xws li diuretics, tshuaj hypoglycemic, khoom noj khoom haus, thiab lwm yam.
Hauv luv luv, mitochondrial abnormalities yog txuam nrog kev nco, tab sis peb yuav tsum tsis txhob txhawj ntau heev vim hais tias peb tuaj yeem tiv thaiv mitochondria, txhim kho lub cev, thiab txhim kho kev nco los ntawm kev hloov peb txoj kev ua neej, thiab kev noj haus, thiab siv cov tshuaj kho mob. Cia peb nquag tiv thaiv thiab txhim kho mitochondrial abnormalities kom muaj lub cev noj qab haus huv thiab lub hlwb ntse. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, 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 ntxiv los txhim kho kev nco
Piv txwv li, metabolic abnormalities yog piav nyob rau hauv Alzheimer's dementia [73], ib tug kab mob ntawm tsis meej thiab complex etiology txuas mus rau lub tsim ntawm extracellular deposits ntawm -amyloid peptide thiab neurofibrillary tangles ofmicrotubular tau protein [74].
Tshaj tawm mitochondrial defects, uas suav nrog organellefragmentation, muaj ntau yam thiab tsis sib xws [73,75].
Qhov loj me me ntawm qhov txawv mitochondrial txawv txav tau piav qhia hauv Alzheimer's tus kab mob confounds cov lus xaus txog seb lawv puas muaj txiaj ntsig rau, lossis feem ntau yog qhov tshwm sim ntawm, tus kab mob tseem ceeb.
Los ntawm qhov tsis sib xws, cov kab mob Parkinson tuaj yeem yog kab mob ntawm mitochondria, vim lawv feem ntau cov kab mob ntawm cov kab mob Parkinsonism tau txuas rau kev hloov pauv ntawm cov noob encodingmitochondrial PINK1 kinase (PARK6) uas pib mitophagy, nrog rau cov thawj coj ntawm cov kab mob principalmitophagy effector ARK2 (Parkin), .
Ib zaug ntxiv, mitochondrial fragmentationis tau tshaj tawm hauv qee qhov, tab sis tsis yog tag nrho, cov lus piav qhia ntawm Parkinson tus kab mob [77], yuav yog vim muaj ntau yam thiab ntau yam etiology.
Thaum kawg, Friedreich's ataxia / spinocerebellardegeneration yog unambiguously ib tug kab mob neurodegenerative nrog ib tug mitochondrial etiology; lub autosomal recessive noob caj noob ces yog nyob rau hauv lub FXN noob uas encodes lub mitochondrial hlau-binding protein, frataxin.
Mitochondrial hlau overload nyob rau hauv Friedreich's ataxiacompromises ATP tsim los ntawm electron thauj saw thiab provokes ntau ROSelaboration [78,79]. Nws tsis paub meej yog tias mitochondrial dynamic dysfunction ua rau, lossis txawm tshwm sim, hauv tus kab mob no [80].
Kev hloov pauv mitochondrial phenotypes hauv cov kab mob neurodegenerative thiab tsis paub meej txog cov kev cuam tshuam ntawm pathophysiological ntawm txawv txav mitochondrial dynamics hais txog qhov xav tau rau kev tshuaj ntsuam platforms ncaj qha cuam tshuam rau tib neeg cov neeg mob.
4. Ntsuas Mitochondrial Dynamics
Qhov yooj yim tshaj plaws tau txais thiab pom tseeb pov thawj rau mitochondrial dysdynamismis txawv txav mitochondrial morphology nyob rau hauv cov duab zoo li qub ntawm cov nyob los yog cov hlwb ruaj khov, feem ntau suav nrog mitochondrial-specific fluorophore.
Qhov feem ntau tshaj tawm mitochondrial structural abnormality yog "fragmentation" los yog structural shortening ntawm organelles, conventionally thiab yooj yim ntsuas raws li txo nam piv (ntev / dav) [81,82].
Txawm hais tias qhov "ib txwm" mitochondrial nam piv nyob ntawm ob qho tib si raws li hom ntawm tes thiab lub cev muaj zog [83], ntsuas nws yog lub tswv yim thiab kev ncaj ncees.
Yog li, qhov txo qis hauv mitochondrial nam piv tau pom nyob rau hauv cov duab daws teeb meem (txo qis / dav lossis luv) feem ntau cuam tshuam txog kev nce hauv mitochondrial fissionto fusion ("fragmentation"), qhov nce ntawm qhov sib piv ("elongation") qhia txog kev nce hauv fusion txheeb ze rau fission. Txawm li cas los xij, qhov hloov pauv qhov piv txwv tsis qhia qhov tshwm sim ntawm dysdynamism, piv txwv li, txawm tias qhov tsis txaus ntseeg yog qhov tshwm sim ntawm kev hloov pauv, lossis fusion, lossis ob qho tib si.
Ntxiv mus, fragmentation ntawm mitochondria nyob rau hauv lub hlwb muaj interconnected mitochondrial tes hauj lwm, xws li fibroblasts, yuav ua tau ib tug ib txwm tivthaiv ntawm mitosis thiab apoptosis [6].
Thaum kawg, luv luv, spherical, los yog "fragmented" mitochondria yog thenorm nyob rau hauv striated nqaij hlwb thiab neuronal axons [7,8,83].Qhov xwm ntawm mitochondrial fusion / fission disequilibrium yog qhov zoo tshaj plaws nthuav tawm los ntawm cov cellimaging, siv ib leeg mitochondrial fluorophore ( Piv txwv li, Mitotracker Liab, Ntsuab, los yog Txiv kab ntxwv), fused hlwb qhia txawv mitochondrial-targeted fluorescent proteins (xws li, Mito-GFP thiab Mito-RFP), los yog ib tug yees duab-switchable mitochondrial fluorophore (xws li, MitoDendra).
Thaum siv ib qho fluorophore, video confocal microscopy tuaj yeem sau cov ntaub ntawv sib xyaw ua ke thiab fission txheej xwm [82].
Thaum cov pab pawg sib txawv ntawm cov hlwb qhia txog mitochondrial-targeted GFP lossis RFP yog fused nrog polyethylene glycol, nws tuaj yeem ua kom muaj nuj nqis mitochondria cov ntsiab lus sib xyaw los ntawm fusion raws li lub sijhawm [84].
Tib txoj hauv kev no yooj yim dua siv cov duab hloov pauv hloov tau mitochondria [85], ua kom muaj cov txheej txheem ntawm mitochondria nyob rau hauv cov hlwb ntawm kev txaus siab rau kev yees duab-hloov ntawm ntsuab mus rau liab fluorescing, thiab txoj hmoo ntawm ib tug neeg mitochondria (xws li, txawm tias lawv tab tom fusing, tab tom fission. , lossis raug thauj mus rau hauv lub cell) los ntsuas lub sijhawm.
Txawm li cas los xij, kev yees duab-switchingapproach xav tau cov cuab yeej tshwj xeeb thiab raug txwv los ntawm cov qauv dhau los.
Txawm hais tias nws muaj peev xwm ua tau los ntawm cov duab zoo li qub ntawm qhov sib txawv ntawm cov ntawv sau npe mitochondria tias cov subpopulations raug thauj mus rau hauv cov hlwb, cov ncauj lus kom ntxaws txog kev txheeb xyuas qhov feem ntau raws li qhov nrawm ntawm motile mitochondria yuav tsum muaj sijhawm-lapse videomicroscopy hauv cov cell nyob lossis cov ntaub so ntswg nrog cov cim ntawm kymographs [{{ 1}}] ib.
Peb lub chaw kuaj pom qhov no ua tau thaum siv rau hauv vitro thiab ex vivo npaj. Tsis tas li ntawd, raws li tau piav qhia hauv qab no, cov tswv yim no tau yooj yim siv rau cov noob caj noob ces manipulatedmouse neurons lossis cov neeg mob tau txais cov hlwb [25,57].
5. Tus neeg mob-derived thawj Fibroblasts pom cov kab mob ntsig txog qhov tsis sib xws hauv Mitochondrial Fission / Fusion
Nws yog qhov nyuaj los tsim ib qho kev tshawb fawb zoo tshaj plaws los ntsuas qhov txawv txav mitochondrial fusion, fission, thiab motility vis a vis lawv kev sib raug zoo rau tib neeg cov kab mob neurodegenerative.
Intuitively, nws zoo nkaus li tias neurons yuav yog qhov zoo tshaj plaws, tab sis thawj cov neeg mob neurons nyuaj kom tau txais, thiab iPSC-derived neurons feem ntau poob cov yam ntxwv ntawm kev kho mob [87,88].
Cov kev sib raug zoo ntawm cov caj ces txawv txav thiab mitochondrial phenotype yog feem ntau txhais tau hais tias siv cov noob caj noob ces knockout.
Germline ablation ntawm Mfn1 los yog Mfn2 yog embryonically tuag [89], tab sis fibroblasts muab los ntawm nas embryos qhia tias impairedmitochondrial fusion tshwm sim los ntawm Mfn1 los yog Mfn2 deletion tsim mitochondrial fragmentation los ntawm unopposed mitochondrial fission; Kev ua haujlwm tsis zoo ntsuas raws li qhov poob ntawm daim nyias nyias polarization yog lwm qhov tshwm sim ntawm qhov tsis zoo mitochondrial contentexchange [90].
Thaum hais txog mitochondrial dysmorphology rau cov hauv paus caj ces, ib qho yuav tsum xav txog qhov sib txawv ntawm cov noob ablation uas abrogates qhia cov neeg xav tias muaj protein ntau thiab yog cov qauv kev sim rau kev kawm txog noob caj noob ces poob ntawm kev ua haujlwm, versusnaturally tshwm sim poob-of-function mutations nyob rau hauv ib qho kev tsis txaus siab ntawm cov protein. exert tseem ceeb suppressive teebmeem.
Yog li, heterozygous ablation ntawm Mfn2gene tau txais txiaj ntsig zoo hauv cov nas [89], thaum feem ntau ntawm cov neeg mob CMT2A muaj ib qho mutant MFN2 allele uas provokes ntxov ntxov neurodegeneration [53,55]. Qhov sib txawv no tau raug ntaus nqi los ntawm kev tawm tsam ntawm ib txwm MFN1 thiab MFN2 ua haujlwm los ntawm ib leeg mutant allele, ua kom nws cov txiaj ntsig ua haujlwm [55–57].
Raws li kev nthuav tawm ntawm tib neeg CMT2A mutants hauv nas recapitulates qee CMT2Aneuronal phenotypes [57,91]. Txawm li cas los xij, qhov tseem ceeb inhibition ntawm ib txwm mitofusins tsis yog qhov kev piav qhia nkaus xwb rau qhov sib txawv ntawm cov noob qoob loo thiab qhia txog kev poob ntawm kev ua haujlwm mutant cuam tshuam: homozygous Mfn2 (los yog Mfn1) noob ablation hauv nas tsis ua rau neurodegeneration; nws provokes ntxov embryonic lethality [89].
Yog li, hloov MFN2 noob ntau npaum li cas los ntawm kev sim "knockout" tsis zoo ib yam li qhia txog kev hloov pauv ntawm MFN2missense.
Tseeb tiag, qhov no tej zaum yuav yog ib txoj hauv kev lom neeg raws li cov noob qoob loo knockdownin Drosophila qauv yog ib qho yooj yim manipulation uas tsis induce qhov ntau npaum li cas los yog loj npaum li cas ntawm compensatory teb raws li kev qhia ntawm genetic mutants [92].
Cov kev soj ntsuam saum toj no txhawb kev siv cov neeg mob los ntawm cov hlwb nqa cov kab mob ua kom muaj qhov tseeb, tsis yog nas cov noob pob txha, rau kev tshawb xyuas cov kab mob ntsig txog mitochondrial phenotypes.
Txawm li cas los xij, recapitulation ntawm prototypical mitochondrial abnormalities nyob rau hauv tus neeg mob-derived fibroblasts yog inconsistent.
Nyob rau hauv tsab xov xwm acompanion [93], peb qhia tau hais tias yuav ua li cas mitochondrial phenotypes yuav evoked bymetabolic stressing nyob rau hauv cov neeg mob dermal fibroblasts los ntawm ib co, tab sis tsis yog txhua txhua, genetic neurodegenerative kab mob.
Tsis tas li ntawd, peb nthuav tawm cov ntaub ntawv txhawb nqa kev siv cov neeg mob los ntawm cov cellas platforms rau kev kuaj tus kheej ntawm mitochondrial-directed therapeutics.
6. Cov ntsiab lus thiab cov lus xaus
Mitochondrial dynamism yog ubiquitous, tab sis tus txheeb ze tus nqi thiab qhov tseem ceeb ntawm mitochondrial fusion, fission, thiab motility txawv raws li cell morphology thiab metabolicrequirements.
Yog li, neurons nrog cov kev xav tau ntawm cov metabolism hauv siab thiab ntev axons muaj qhov tshwj xeeb dynamic profiles thiab tshwj xeeb tshaj yog raug rau dynamic dysfunction. Mitochondrialphenotypes nyuaj rau kev soj ntsuam hauv tib neeg cov kab mob neurodegenerative vim humanneurons tsis tau yooj yim.
Yav dhau los thiab nrog cov ntaub ntawv qhia tau hais tias kev coj noj coj ua ntawm tib neeg dermal fibroblasts tuaj yeem raug ntxias kom pom cov kab mob neurodegenerative ntsig txog mitochondrial fusion-fission phenotypes los ntawm kev yuam mitochondrial metabolism los ntawm qhov yooj yim maneuver ntawm hloov galactose rau qabzib hauv kab lis kev cai nruab nrab.
Ntxiv mus, tib lub fibroblasts tuaj yeem ncaj qha reprogrammed rau hauv cov neurons uas retainhallmark mitochondrial abnormalities, nrog rau dysmotility, uas yog qhov zoo tshaj plaws ntsuas inneuronal axons.
Peb xav tias kev sib koom ua ke ntawm cov platforms no nrog cov qauv nas caj ces, raws li tau piav qhia hauv daim duab 4, yuav yog ib qho txiaj ntsig zoo ntawm kev ntsuas cov neeg sib tw kho mob hauv ntau cov kab mob ntawm cov kab mob neurodegenerative uas nthuav tawm cov yam ntxwv mitochondrial abnormalities, lossis ntawm cov neeg mob sib txawv rau kev kho tus kheej.
Sau Kev Koom Tes: Conceptualization, GWDII; kev sau ntawv-keeb kwm kev npaj, GWDII; sau- tshuaj xyuas thiab kho, GWDII thiab XD; saib xyuas, GWDII; Kev nrhiav nyiaj txiag, GWDII.Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Cov Nyiaj Txiag: Cov kev tshawb fawb no tau txais nyiaj los ntawm NIH R35135736, R42NS115184, thiab kev tshawb fawb nyiaj txiag los ntawm Lub Koom Haum Muscular Dystrophy. APC tau txais nyiaj los ntawm NIH R35135736.
Institutional Review Board Statement: Tsis siv tau.
Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.
Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.
Kev tsis sib haum xeeb ntawm kev txaus siab: GWD yog Philip- thiab Sima K. Needleman-tau txais txiaj ntsig xibfwb ntawm WashingtonUniversity hauv St. Louis thiab yav dhau los Scholar-Innovator tau txais txiaj ntsig ntawm Harrington Discovery Institute.
GWD yog tus tsim khoom ntawm patents uas tau muab thiab tseem tos los ntawm Washington University hauv St. Louisand Mitochondria Emotion, Inc. npog cov molecule mitofusin activators me me, thiab yog tus tsim ntawm Mitochondria hauv Motion, Inc., Saint Louis-based biotech tshawb fawb thiab kev loj hlob tuam txhab tsom mus rau txhim kho mitochondrial kev lag luam thiab kev tawm dag zog hauv cov kab mob neurodegenerative.
Thefunders tsis muaj lub luag haujlwm hauv kev tsim kev kawm; hauv kev sau, txheeb xyuas, lossis txhais cov ntaub ntawv; hauv kev sau cov ntawv sau, lossis hauv kev txiav txim siab tshaj tawm cov txiaj ntsig.
Cov ntaub ntawv
1. Txoj kab, N.; Martin, W. Lub zog ntawm genome complexity. Xwm Txheej 2010, 467, 929–934. [CrossRef]
2. Grey, MW Mitochondrial evolution. Caij nplooj ntoos hlav Harb. Kev xav. Biol. Xyoo 2012, 4, 011403. [CrossRef]
3. Mishra, P.; Chan, DC Mitochondrial dynamics thiab qub txeeg qub teg thaum lub sij hawm cell division, kev loj hlob thiab kab mob. Nat. Rev. Mol.Cell Biol. 2014, 15, 634–646. [CrossRef] [PubMed]
4. Chen, H.; Chan, DC Mitochondrial dynamics-Fusion, fission, txav, thiab mitophagy-Nyob rau hauv cov kab mob neurodegenerative.Hum. Mol. Genet. Xyoo 2009, 18, R169–R176. [CrossRef] [PubMed]
5. Dorn, GW, II. Evolving Concepts ntawm Mitochondrial Dynamics. Annu. Rev. Physiol. Xyoo 2019, 81, 1-17. [CrossRef] [PubMed]
6. Khob, R.; Bilyy, R. Mitochondrial dynamics thaum caij tsheb kauj vab. Apoptosis 2016, 21, 1327–1335. [CrossRef] [PubMed]
7. Nkauj, M.; Dorn, GW, II. Mitoconfusion: Noncanonical ua haujlwm ntawm dynamism yam hauv static mitochondria ntawm lub plawv. CellMetab. 2015, 21, 195–205. [CrossRef]
8. Dorn, GW, II. Mitochondrial dynamism thiab kab mob plawv: Hloov cov duab thiab hloov pauv. EMBO MOL. Med. Xyoo 2015, 7, 865-877. [CrossRef]
9. MacAskill, AF; Kittler, JT Tswj kev thauj mitochondrial thiab localization hauv neurons. Trends Cell Biol. 2010, 20, 102–112 [CrossRef]
10. Sheng, ZH; Cai, Q. Mitochondrial thauj hauv neurons: cuam tshuam rau synaptic homeostasis thiab neurodegeneration. Nat. Rev. Neurosci. 2012, 13, 77–93. [CrossRef]
11. Pareyson, D.; Piscosquito, G.; Maulaunais, I.; Salsano, E.; Zeviani, M. Peripheral neuropathy hauv mitochondrial mob. Lancet Neurol.2013, 12, 1011–1024. [CrossRef]
12. Vaaj, T.; Langer, T. Mitochondrial Dynamics thiab Metabolic Regulation. Trends Endocrinol. Metab. 2016, 27, 105–117. [CrossRef][PubMed]
For more information:1950477648nn@gamil.com
