Predicting Mitochondrial Dynamic Behavior hauv Genetically Defined Neurodegenerative Diseases Part 1

Abstract:

Mitochondrial dynamics encompass mitochondrial fusion, fission, thiab txav. Mitochondrial fission thiab fusion yog zoo li ubiquitous, whereas mitochondrial zog yog tshwj xeeb tshaj yog tseem ceeb rau organelle thauj los ntawm neuronal axons.

Mitochondria yog ib feem tseem ceeb ntawm lub cell. Mitochondria zoo li lub "zog factories" ntawm tes, noj lub zog ntawm cov zaub mov thiab hloov mus rau hauv adenosine triphosphate (ATP) rau lub cell siv. Mitochondria tseem ceeb heev rau ntau yam ntawm lub cev, suav nrog kev noj qab haus huv ntawm lub plawv thiab cov leeg thiab kho cov hlwb puas.

Txawm li cas los xij, ib qho ntawm ntau qhov tshiab thiab zoo siab txog qhov kev ua haujlwm ntawm mitochondria yog nws txoj kev sib raug zoo nrog kev nco. Qee qhov kev tshawb fawb tau pom tias kev ua haujlwm ntawm mitochondria tsis txwv rau kev muab lub zog xav tau los ntawm lub xov tooj ntawm tes. Lawv kuj tuaj yeem cuam tshuam rau peb cov kev txawj ntse, suav nrog peb lub cim xeeb.

Ib txoj kev tshawb nrhiav pom tias kev puas tsuaj mitochondrial tuaj yeem ua rau muaj kev cuam tshuam txog kev nco. Cov kws tshawb fawb tseem pom tias los ntawm kev nce cov mitochondria thiab kho cov mitochondria puas, lawv tuaj yeem txhim kho kev nco hauv cov nas. Cov kev tshawb pom no ua rau peb pom zoo tias muaj kev sib raug zoo ntawm mitochondrial muaj nuj nqi thiab kev nco.

Kev noj qab haus huv ntawm mitochondria kuj tseem ceeb heev rau kev nco ua haujlwm ntev hauv tib neeg. Qee qhov kev tshawb fawb tau pom tias thaum tib neeg muaj hnub nyoog, kev ua haujlwm ntawm mitochondria poob qis, thiab yog li ntawd, qee qhov kev paub txog kev xav kuj cuam tshuam. Qhov no suav nrog cov kab mob xws li dementia thiab Alzheimer's disease.

Tau kawg, kev tshawb fawb ntxiv yog xav tau los txiav txim siab lub luag haujlwm ntawm mitochondria hauv tib neeg lub cim xeeb. Txawm li cas los xij, cov kev tshawb fawb peb tau hais los saum toj no tseem muab rau tib neeg nrog qee cov ntaub ntawv tseem ceeb zoo nkauj. Los ntawm kev tiv thaiv peb cov mitochondria, peb tuaj yeem tiv thaiv peb lub cim xeeb zoo dua, uas yuav pab peb nkag siab zoo txog kev tiv thaiv thiab kho cov kab mob cuam tshuam nrog kev paub txog kev ua haujlwm.

Hauv ntej, mitochondria yog ib feem tseem ceeb ntawm peb lub cev thiab lawv ua lub luag haujlwm tseem ceeb hauv kev muab lub zog. Ntxiv mus, qhov kev tshawb fawb tshiab qhia tau hais tias kev ua haujlwm mitochondrial tuaj yeem cuam tshuam rau tib neeg kev nco. Peb yuav tsum ntxiv dag zog rau peb txoj kev nkag siab txog kev ua haujlwm mitochondrial thiab tiv thaiv nws kom tsim nyog kom peb thiaj li txo tau txoj kev pheej hmoo ntawm kev nco txog kab mob thiab ua lub neej zoo. Nws tuaj yeem pom 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 oxidative thiab inflammatory teb nyob rau 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 10 txoj hauv kev los txhim kho kev nco

Ntawm no, peb tshuaj xyuas lub luag haujlwm ntawm cov txheej txheem sib txawv mitochondrial dynamic hauv mitochondrial kom muaj nuj nqis thiab kev tswj kom zoo, hais txog kev cuam tshuam ntawm cov paj hlwb hauv Charcot-Marie-Tooth kab mob hom 2A, amyotrophic lateralsclerosis, Friedrich's ataxia, dominant optic atrophy, thiab Hungarian atrophy. 'cov kab mob.

Ntxiv nrog rau cov txheej txheem thiab cov tswv yim, peb tshawb nrhiav hauv kev nthuav dav ntau yam kev sib txawv rau kev ntsuas mitochondrial dynamic dysfunction hauv vitro, piav qhia yuav ua li cas cov txiaj ntsig los ntawm cov ntaub so ntswg kev coj noj coj ua tuaj yeem siv rau kev nkag siab zoo ntawm mitochondrial dysdynamism hauv tib neeg cov kab mob neurodegenerative, thiab qhia seb qhov kev sim no yuav ua li cas. siv los ntsuas cov neeg sib tw kho mob hauv cov kab mob sib txawv lossis cov neeg mob sib koom ua ke tib yam kev kuaj mob.

Ntsiab lus: mitochondrial dynamics; kab mob neurodegenerative; tshuaj mitofusin.

1. Taw qhia

Aerobic lub neej nyob ntawm mitochondrial oxidative phosphorylation los tsim ATP uas ua rau cov txheej txheem lom neeg feem ntau.

Kev sib raug zoo ntawm cov tswv tsev thiab mitochondria, uas cov kab mob cov poj koob yawm txwv tau nkag mus rau cov kab mob thaum ntxov unicellular kwv yees li 1.5 billion xyoo dhau los [1,2], yog lub hauv paus rau kev hloov pauv ntawm ntau lub neej hauv ntiaj teb.

Qhov kev sib raug zoo no yog inextricable, vim hais tias tus tswv tsev tsis tuaj yeem muaj sia nyob tsis muaj lawv cov neeg nyob hauv mitochondria, thiab mitochondria tau xa tawm ~ 99% ntawm lawv cov DNA los tuav cov genomes nuclear.

Orchestrating contextually tsim nyog tus cwj pwm tseem ceeb rau metabolic homeostasis, mitochondrial biogenesis, thiab programmed hloov senescent mitochondria (mitophagy) los yog hlwb (apoptosis) xav kom mitochondria thiab host cells sib txuas lus thaum tswj kev tswj hwm tus kheej ntawm tus kheej organelles uas yog keeb kwm ntawm lawv cov kab mob progenitors.

Mitochondrial dynamism yog ib qho tseem ceeb ntawm cov cell-organelle kev sib koom tes [3].Mitochondrial dynamics muaj xws li mitochondrial fission, fusion, thiab motility [4,5].

Nyob rau theem kev soj ntsuam, cov no yog cov txheej txheem sib txawv uas nws cov haujlwm yog txiav txim los ntawm hom cell thiab cov ntsiab lus pathophysiological. Yog li, mitochondria nyob rau hauv quiescent fibroblasts yog ib feem ntawm cov kev sib txuas sib txuas heev uas nyob rau hauv mitochondrial fusion thiab fissionmediate nruam kev hloov kho ntawm lub collective; Kev xa cov subcellular ntawm ib tus neeg mitochondria tsis tshua muaj (~ 2% -4%).

Txawm li cas los xij, ua ntej fibroblast mitosis thiab cytokinesis, mitochondrial network tau dhau los ua kev sib cais ntawm kev sib cais, ua rau ib nrab ntawm cov neeg ua haujlwm organelles raug coj mus rau txhua tus ntxhais ntawm tes ua ntej [6].

Los ntawm qhov sib txawv, mitochondria ntawm lub plawv thiab pob txha myocytes zoo li zoo li qub pawg ntawm cov tib neeg cov kab mob nyob nruab nrab ntawm myofilaments; fusionand fission tsis tshua muaj [7,8].

Hauv cov neurons, mitochondrial dynamism tshwm sim raws li qhov chaw subcellular: mitochondria nyob rau hauv neuronal soma muaj xws li nyob ruaj ruaj perinuclear pawg, mitochondria nyob rau hauv cov txheej txheem neuronal yog nyob rau hauv cov pawg me (~ 70%) los yog tseem tab tom ua rau kev thauj mus los los yog kev thauj mus los (~ 30%). , thiab mitochondria nyob rau hauv synaptic neuromuscular junctions zoo li nyob ruaj ruaj ib tus neeg organelles [9,10].

Kev sib txawv ntawm cov qauv mitochondrial thiab kev siv sib txawv ntawm mitochondrial dynamics raws li hom cell thiab subcellular qhov chaw yuav piav qhia vim li cas mitochondrial dynamic dysfunction feem ntau cuam tshuam rau lub paj hlwb [1l].

Ntawm no, peb muab cov ntsiab lus ntawm mitochondrial dynamism thiab dynamic dysfunction raws li lawv muaj feem xyuam rau genetic neurodegenerative kab mob thiab piav qhia txog ib txoj hauv kev rau lawv qhov kev ntsuam xyuas hauv preclinical hauv vitro thiab hauv vivo kev sim tshuab.

2. Mitochondrial Fusion, Fission, thiab Motility

Mitochondrial fission, fusion, thiab motility tau yooj yim pom raws li cov txheej txheem ntawm tus kheej. Cov txheej txheem molecular thiab cov ntsiab lus tseem ceeb kho mitochondrialdynamism tau nkag siab zoo thiab yog cov ntsiab lus ntawm ntau cov ncauj lus kom ntxaws [4,5,12,13].

Qhov tseem ceeb, mitochondrial fission, fusion, thiab kev thauj mus los yog kev sib raug zoo ntawm lub cev thiab kev siv tshuab thiab muaj kev sib koom tes tswj. Lub fission ntawm noj qab nyob zoo mitochondria yog ib tug txhais tau tias rau organelle replication, recapitulatingancestral kab mob yug me nyuam [14].

Txhawm rau kom suav cov xov tooj ntawm tes mitochondria, cov niam txiv noj qab haus huv organelles duplicate lawv cov mitochondrial genomes thiab undergo symmetrical replicaative fission rau hauv ob tug ntxhais mitochondria, txhua tus tuaj yeem dhau los ua tus tswv cuab ntawm tus tswv ntawm tes mitochondrial collective los ntawm: 1.

"Growing" raws li ib tug neeg organelle los ntawm transcription thiab txhais ntawm nws 13 protein-coding mitochondrial DNA (mtDNA) genesand incorporation ntawm pua ​​pua ntawm nuclear-encoded mitochondrial proteins (collectivelytermed mitochondrial biogenesis); lub 2.

Koom nrog, los ntawm kev sib txuas nrog lub network interconnectedmitochondrial uas twb muaj lawm. Yog li, kev sib xyaw ua ke ntawm mitochondrial fission ua rau ob qho tib si tomitochondrial biogenesis thiab mitochondrial fusion (Daim duab 1).

Los ntawm qhov sib txawv, asymmetric fission ntawm tus raug mob / senescent niam txiv mitochondrion yog cov txheej txheem ntawm kev xaiv tshem tawm cov khoom puas los ntawm lawv kev sib cais thiab sib cais rau hauv ib qho ntawm cov ntxhais organelles; tus ntxhais no thaum kawg raug tshem tawm thiab nws cov ntsiab lus rov ua dua [15].

Tom qab asymmetric fission, tus ntxhais noj qab haus huv loj dua mitochondrion tuaj yeem dhau los ntawm kev loj hlob ntawm biogenic los yog kev sib xyaw ua ke, ib yam li cov ntxhais ntawm kev rov ua dua tshiab.

Txawm li cas los xij, tus ntxhais me me mitochondrion uas muaj cov khoom puas thiab feem ntau nthuav tawm qhov kev tshem tawm ntawm ∆Ψm (lub puab membraneelectrochemical proton gradient uas ua rau ua pa nyuaj ua haujlwm) yog tiv thaiv los ntawm kev fusion thiab tsis yog tsom rau kev tshem tawm ntawm mitophagy (mitochondrial-specific autophagy).

Yog li, asymmetric mitochondrial fission ob qho tib si enables thiab suppressesmitochondrial fusion, biogenesis, thiab mitophagy, nyob ntawm seb qhov kev noj qab haus huv ntawm tus ntxhais mitochondria (Daim duab 1).

Raws li, mitochondrial fission yog ib qho tseem ceeb tomitochondrial kom muaj nuj nqis tswj (ntawm replicaative fission thiab biogenesis) thiab mitochondrialquality tswj (ntawm asymmetric fission thiab mitophagy).

Vim li no, nws yuav raug kwv yees tias kev cuam tshuam lossis dysregulating mitochondrial fission yuav cuam tshuam rau mitochondrial homeostasis.

Raws li qhov kev xav no, qhov tsis tshua muaj tshwm sim, tuag taus, thiab ntau yam kab mob metabolic derangement tau txuas rau kev hloov pauv ntawm qhov tseem ceeb ntawm cov protein fission, DRP1 [16-19], txawm hais tias muaj kev hloov pauv tseem ceeb hauv DNM1L genecan kuj ua rau muaj kev cuam tshuam ntawm optic atrophy (DOA). phenotype [20].

Mitochondrial fusion yog lub hauv paus rau postreplicative mitochondrial maturation thiab kev koom ua ke ntawm tus ntxhais organelles rau hauv mitochondrial tes hauj lwm. Mitochondrial fusion kuj tseem yog cov txheej txheem sib koom ua ke uas tswj cov kev ua haujlwm ntawm ib tus neeg mitochondria.

Cov txheej txheem no yog raws li lub tswv yim ntawm kev kho los ntawm kev sib sau ua ke [21] (Daim duab 1). Piv txwv li, mitochondria muaj ntau cov ntawv luam tawm ntawm lawv cov mtDNA genomes, uas ua rau muaj kev hloov pauv hauv lub sijhawm.

Yog tias mtDNA hloov pauv lub nra hnyav heev, asymmetric fission tuaj yeem ua haujlwm rau sequester thiab tshem tawm cov genomes ua txhaum (vide supra). Txawm li cas los xij, thaum cov kev hloov pauv ntawm mtDNA tsis txaus ua rau ua rau muaj kev cuam tshuam tsis zoo, kev puas tsuaj mitochondria tuaj yeem fuse thiab pauv cov genomes, yog li muab cov qauv tsis zoo rau kev sib nrig sib kho [22].

Tib lub tswv yim ntawm kev kho los ntawm kev ntxiv (lossis dilution) siv rau mitochondrial proteins thiab daim nyias nyias [23].

Lub luag haujlwm tseem ceeb ua si los ntawm mitochondrial fusion hauv kev saib xyuas organelle yog epitomized nyob rau hauv cov hlwb dual tsis muaj nyob rau hauv sab nrauv mitochondrial membrane fusion proteins mitofusin (MFN) 1 thiab 2, uas tsis yog tsuas yog nthuav tawm mitochondrial fragmentation los ntawm unopposed fission tab sis kuj mitochondrial depolarization (mutochondrial depolarization). kho kom haum xeeb [24,25].

Mitochondrial motility, thiab tshwj xeeb tshaj yog qhia kev thauj mus los ntawm cov txheej txheem neuronal, tsis to taub tag nrho tshaj li mitochondrial fission thiab fusion. Miro proteins ntawm cov kab mob sab nraud cuam tshuam nrog cov calcium-dependent yam nrog Trak1/Miltonadaptor proteins rau ob peb mitochondria mus rau dynein (retrograde trafficking) los yog kinesin-1(antegrade trafficking) tsev neeg lub cev muaj zog proteins uas thauj mitochondria nrog cellular/axonal microtubules ,27] (Daim duab 2 mitochondrial thauj).

Daim duab 2. Mitochondrial muaj nuj nqi thiab motility yog txhais los ntawm subcellular qhov chaw nyob rau hauv neurons.

Schematicdepicts neuronal soma rau sab laug, axon nyob rau hauv qhov chaw, thiab dendrites nrog synapses rau sab xis. Inset qhia Miro txuas ib mitochondrion, ntawm adapter protein Trak1, rau dynein los yog kinesin motor proteins fortransport raws axonal microtubules.

Ntawm no, cov kev hloov hauv zos hauv cytoplasmic dawb calcium, raws li pom nyob rau hauv lub cev axonalinjury, tswj mitochondrial thauj thiab lo lus uas peb [27,28].

Lwm yam pathophysiologicaldeterminants uas xaiv mitochondria rau kev thauj lossis coj lawv mus rau cov chaw tshwj xeeb tau raug txiav txim siab, suav nrog Disrupted In Schizophrenia 1 (DISC1) cov protein uas hloov pauv cov tshuaj antegrade kinesin-mediated mitochondrial kev lag luam los ntawm kev cuam tshuam nrog GTP-bound Miro1 [29] thiab cov yam tsis raug txheeb xyuas. thiab kev ua si [30].

Dab tsi tau pom tseeb yog tias kev hloov pauv pathological hauv qhov sib npaug ntawm mitochondrial fissionand fusion, nquag nrog kev cuam tshuam hauv kev lag luam mitochondrial, yog qhov cim ntawm ntau qhov chaw kho mob thiab sim neurodegenerative syndromes [4,10,31–34].

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