Los ntawm Cov Qauv Thiab (Dys) Kev Ua Haujlwm Ntawm ATP Synthase rau Deficiency hauv Hnub Nyoog Cov Kab Mob Pa

Abstract:

ATP synthase yog ib qho mitochondrial inner membrane complex uas nws txoj haujlwm tseem ceeb rau cell bioenergy, ua lub luag haujlwm rau kev hloov pauv ntawm ADP rau hauv ATP thiab ua lub luag haujlwm hauv lub koom haum inmitochondrial cristae morphology.

Nyob rau hauv xyoo tas los no, ntau thiab ntau cov kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm mitochondrial puab membrane complex thiab nco. Lub mitochondrial puab membrane complex yog ib tug complex ntawm ntau yam proteins nyob rau hauv lub puab mitochondrial membrane. Nws yog lub luag haujlwm tseem ceeb rau kev tswj cov txheej txheem xws li lub zog metabolism thiab kev tuag ntawm tes hauv cov hlwb. Kev nco yog hais txog tib neeg lub hlwb lub peev xwm los kawm, nco qab, thiab khaws cov stimuli sab nraud, kev paub, thiab tej yam. Txawm hais tias ob qho tib si zoo li tsis cuam tshuam, kev tshawb fawb tsis ntev los no tau pom tias mitochondrial inner membrane complex yog inextricably txuas rau kev nco.

Ua ntej, mitochondrial inner membrane complex plays lub luag haujlwm tseem ceeb hauv lub zog ntawm lub hlwb hlwb. Thaum tib neeg lub cev nyob rau hauv lub xeev ntawm kev xav, kev kawm, thiab kev nco, lub hlwb yuav tsum muaj ntau lub zog los tswj kev ua haujlwm ib txwm muaj. Lub mitochondrial inner membrane complex tuaj yeem ua kom muaj zog hauv cov hlwb los ntawm kev tswj cov piam thaj metabolism hauv mitochondria, ua rau lub hlwb ua haujlwm ib txwm nyob rau hauv kev xav thiab kev nco.

Thib ob, mitochondrial puab membrane complex kuj tuaj yeem cuam tshuam kev nco los ntawm kev tswj hwm ATP synthesis. ATP yog ib qho intracellular zog molecule uas ua lub luag haujlwm tseem ceeb hauv kev ua haujlwm ntawm cov hlwb. Sab hauv mitochondrial membrane complex tswj cov synthesis thiab theem ntawm ATP, yog li nws tuaj yeem cuam tshuam rau tib neeg lub cim xeeb los ntawm kev tswj hwm qib ntawm ATP hauv cell. Qee qhov kev tshawb fawb ntsig txog kuj tau qhia tias thaum qib ATP hauv cov hlwb siab, tib neeg txoj kev kawm thiab kev nco muaj peev xwm yuav txhim kho tau zoo.

Thaum kawg, mitochondrial inner membrane complexes tseem tuaj yeem cuam tshuam txoj kev tuag ntawm hlwb hlwb. Thaum lub hlwb hlwb nyob rau hauv kev muaj sia nyob ntau dua rau ntau yam laj thawj, txoj kev tuag tuaj yeem tshwm sim tau yooj yim. Lub mitochondrial inner membrane complex tuaj yeem tiv thaiv txoj sia nyob ntawm lub hlwb los ntawm kev tswj cov txheej txheem xws li apoptosis thiab autophagy, yog li tswj hwm tib neeg lub cim xeeb.

Yog li, cov kev tshawb fawb saum toj no qhia tau hais tias muaj kev sib txuas tsis sib xws ntawm mitochondrial inner membrane complexes thiab nco. Los ntawm kev tswj hwm kev ua haujlwm ntawm mitochondrial inner membrane complex, tib neeg tuaj yeem txhim kho lawv lub cim xeeb, yog li txhim kho lawv txoj kev kawm thiab kev ua haujlwm zoo, thiab ua rau lub neej zoo dua. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola 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 los ntawm ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Lub enzyme yog tsim los ntawm 18 protein subunits, 16 nuclear DNA (nDNA) encoded, thiab ob mitochondrial DNA (mtDNA) encoded, koom nyob rau hauv twodomains, FO thiab F1. Pathogenetic variants nyob rau hauv cov noob encoding structural subunits los yog los ua ke factories yog lub luag hauj lwm rau cov neeg tuag kab mob.

Cov pov thawj tshwm sim kuj tseem qhia txog lub luag haujlwm ntawm ATP-synthasein neurodegenerative kab mob xws li Parkinson's, Alzheimer's, thiab cov kab mob hauv lub cev xws li Amyotrophic Lateral Sclerosis.

Kev hloov pauv tom qab kev hloov pauv, kev hloov pauv hloov pauv hloov pauv ntawm ATP geneexpression thiab qib protein, thiab cov txheej txheem ntawm mitochondrial hloov pore tau suav tias yog lub luag haujlwm rau kev tuag ntawm cov cell hauv vivo thiab hauv vitro qauv rau cov kab mob neurodegenerative. Hauv qhov kev tshuaj xyuas no, peb yuav tshawb xyuas ATP synthase sib dhos thiab ua haujlwm hauv lub cev thiab cov kab mob pathological los ntawm kev xa mus rau cov kev tshawb fawb cryo-EM tsis ntev los no thiab los ntawm kev tshawb nrhiav tib neeg cov qauv kab mob.

Ntsiab lus: mitochondria; ATP synthase; cell tuag; Cov kab mob neurodegenerative.

1. Taw qhia

Cell ciaj sia nyob rau hauv lub zog tsim nyob rau hauv daim ntawv ntawm ATP (adenosine triphosphate) molecules, lub universal zog txiaj rau tag nrho cov nyob. Lub mitochondria, hu ua lub cellular powerhouse, yog lub zog tsim organelles ntawm tes [1].

Cov yam ntxwv tshwj xeeb yog qhov muaj DNA (mtDNA) nkaus xwb los ntawm leej niam.Qhov kev tswj hwm ntawm ob qho tib si nuclear (nDNA) thiab mtDNA yog lub luag haujlwm rau encoding ib ncig ntawm 1500 proteins, ua lub luag haujlwm hauv mitochondrial muaj nuj nqi thiab kev saib xyuas.

ATP synthase (EC 3.6.1.34), tseem hu ua complex V, yog tsim los ntawm 18 protein subunits, 16 nDNAencoded thiab ob mtDNA encoded. Lub luag haujlwm tseem ceeb yog kev hloov pauv ntawm ADP rau hauv ATP, ua tsaug rau proton gradient generated los ntawm complexes I mus rau IV thiab activating rotormechanism. Ua ib qho tseem ceeb hauv cov hlwb aerobic, cov qauv hauv paus thiab cov txheej txheem catalytic ntawm ATP synthase tau txais txiaj ntsig zoo thoob plaws hom, los ntawm cov kab mob mus rau eukaryotes [2,3].

Tsis tas li ntawd, cov enzyme tau koom nrog hauv morphology ntawm mitochondria los ntawm kev txhawb nqa cov txheej txheem ntawm cov txheej hauv daim nyias nyias cristae, ib qho kev tshwm sim uas hloov zuj zus mus suav nrog daim nyias nyias "supernumerary" subunits [4].

ATP synthase yog tus neeg koom tes tseem ceeb hauv cell bioenergeticmachinery [5] los ntawm kev qhia txog qhov tseem ceeb ntawm "enzyme ntawm lub neej". Txwv tsis pub, mitochondrial dysfunction yuav tshwm sim los ntawm molecular hloov ntawm ATP synthasefunction uas tshwm sim nrog "supernumerary" subunit hloov kho los ntawm stimulating ntau hom kev tswj ntawm tes tuag [6].

Lub physio (patho) lub ntsiab lus tshwm sim tuaj yeem suav nrog Ca2+- nyob ntawm kev hloov pauv permeability ntawm mitochondrial inner membrane mus rau ions thiab solutes nrog molecular loj txog li 1.5 KDa [7–9]. Cov ntaub ntawv pov thawj qhia txog lub luag haujlwm ntawm qhov ntxim nyiam enzyme complex raws li qhov tseem ceeb ntawm cov molecular thiab enzymatic hloov ntawm lub neej ntawm tes thiab kev tuag thiab ua rau nws muaj kev ntxim nyiam raws li lub hom phiaj tshuaj thiab tshuaj tsim [10].

Txawm li cas los xij, mitochondria tuaj yeem koom nrog hauv ob qho tib si kev loj hlob thiab kev tuag ntawm tes, nyob rau hauv uas cov yam ntxwv yog nyob ntawm qhov tshwm sim uas tsim cov kev coj ua tau zoo channel paub tias yog mitochondrial permeability transition pore (mPTP) [11].Qhov nce hauv cov neeg laus hauv cov niaj hnub no. haiv neeg tau dhau los ua teeb meem cuam tshuam ntawm kev lag luam kev lag luam vim muaj ntau dua ntawm cov hnub nyoog ntsig txog neurodegenerativediseases.

Yog li ntawd, txoj kev loj hlob ntawm cov tswv yim tshiab tsom rau cov yam ntxwv ntawm cov kab mob no yog lub ntsiab lus raws sijhawm. Tsis zoo zog homeostasis txuas mus rau mitochondrial dysfunction springs los ntawm ib tug impaired los yog tsis xws luag zog transduction system, uas ua rau lub mainbiochemical kev puas tsuaj nyob rau hauv ntau yam genetic thiab neuropsychiatric kab mob [12].

Hauv ntau cov kab mob neurodegenerative, protein aggregation thiab mitochondrial dysfunction yog ob yam kab mob ua rau lub luag haujlwm rau qhov pib ntawm cov kab mob hnub nyoog.Xwb, mitochondrial structural thiab functional defects yog tshwm sim los ntawm mitochondrialdynamics impairment ua rau neurodegeneration thiab laus, kab mob Alzheimer's. (PD), amyotrophic lateral sclerosis (ALS), thiab Huntington's disease (HD).

Qhov inhibition ntawm ntau fission txo cov cell tuag txoj kev tshwm sim los ntawm mitochondrial dysfunction [13]. Yog li ntawd, lub morphology ntawm mitochondria yog intimately koom nyob rau hauv kev laus los ntawm kev nthuav tawm lub hnub nyoog ntawm kev hloov pauv hauv daim nyias nyias.

TheATP synthase koom nrog hauv kev tsim mitochondrial cristae morphology [4]. ATP synthase dimers tau teem rau hauv kab ntev ntawm qhov kawg ntawm cristae ua ke nrog MICOS (mitochondrial contact site thiab cristae organize system) complex ntawm cristae junctions thiab koom tes los ntawm kev tawm tsam los ntawm daim nyias nyias curvature rau cristae morphology [14].

Themembrane remodeling tshwm sim los ntawm disassembly ntawm lub koom haum supramolecular ntawm ATP synthase zoo li lub puab-membrane vesiculation ntawm qub mitochondria. Nyob rau hauv tag nrho zoo li, lub cristae luv luv thiab vau nrog ATP synthase dimers dissociation uas txo cov convex membrane curvature nyob rau hauv lub puab mitochondrial membrane (IMM).

Lub hnub nyoog cuam tshuam txog kev poob qis hauv bioenergetics, redox homeostasis, thiab mitochondrial calciumcapacity ua rau kom nrawm pathogenesis. Tseeb, qhov ua tsis tiav ntawm lub koom haum ntawm lub zog khiav hauv cov hlwb yog lub hauv paus ntawm kev lom zem ntawm cov kab mob hauv kev laus [15].

2. Cov qauv thiab kev ua haujlwm ntawm ATP Synthase

ATP synthase yog ib qho oligomeric complex nyob rau hauv lub zog-transducingmembranes ntawm mitochondria, chloroplasts, thiab kab mob [16]. Lub transmembrane protonmotive force (∆p) yog ua haujlwm los ntawm ATP synthase ua lub zog.

Lub ∆p drives themechanical rotary mechanism los ntawm cov membrane-embedded feem ntawm cov enzyme (FO) txuas mus rau chemomechanical synthesis ntawm ATP los ntawm ADP thiab Pi ntawm hydrophilicF1 feem (Daim duab 1). Ntxiv mus, lub ∆p generated los ntawm substrate oxidation thaum lub sij hawm mitochondrial respiration yog dissipated los ntawm FO nrog torque tiam ntawm lub rotor tso cai rau kev koom tes ntawm ATP binding mechanism ntawm catalytic chaw thaum lub sij hawm ATP ntau lawm [17]. Hloov pauv, thaum ATP hydrolysis, enzyme ua haujlwm rov qab ua H + twj tso kua mis thiab rov ua kom lub zog IMM.

Qhov no bifunctional zog kis tau tus mob mechanism ntawm ATP synthase yog tshwj xeeb nyob rau hauv biological systems [18]. Lub membrane-bound rotor muaj ib tug c-ntiv nplhaib ntawm yim zoo tib yam helical hairpin lug nyob rau hauv ze ze nrog lub subunit.

Lub c-ring stoichiometry yog hom-nyob thiab nruj ntsig txog tus nqi mitochondrialbioenergetic [2,3].

Txhua lub c subunit muaj H+-binding site uas tau txiav txim siab los ntawm kev txuag acidicside saw (Glu58 hauv cov tsiaj nyeg) ntawm C-terminal helix nyob nruab nrab ntawm IMM uas yogdicyclohexylcarbodiimide-sensitive thiab tseem ceeb hauv ATP synthesis lossis hydrolysis.

H + translocation yuav siv qhov chaw ntawm ob lub aqueous ib nrab-channels hauv ib lub subunit [19], nyob rau hauv uas asymmetric kev npaj dictates ob opposite kev sib hloov cov lus qhia nyob rau hauv lub ATP synthesis thiab hydrolysis [20]. Kev sib hloov ntawm c-ntiv nplhaib yog xa ncaj qha mus rau F1 domain bythe asymmetrical central stalk (sau ntawm , δ, thiab ε subunit) txuas los ntawm "ko taw" rau c-ntiv nplhaib. Lub subunit ntawm lub hauv paus stalk penetrates raws lub hauv paus axis ntawm lub F1 sau uas muaj peb tsis-catalytic - thiab peb catalytic -subunits alternate ina hexameric ( ) 3 qauv nyob ib ncig ntawm lub hauv paus stalk (Daim duab 1).

Cov chaw catalytic tau muab tso rau ntawm lub subunits ntawm qhov sib txuas nrog cov subunits.Txhua lub subunit catalyzes cov tshuaj tiv thaiv ntawm synthesis los yog hydrolysis uas tau tsav los ntawm ∆p los yog ATP phosphorylation muaj peev xwm, feem. Thaum lub sij hawm synthesis, qhov kev sib hloov ntawm lub rotor saib los ntawm sab matrix yog nyob rau hauv anticlockwise hom. Conversely, lub clockwise tig ntawm lub rotor txhawb ATP hydrolysis.

Txhua lub subunit hloov pauv ATP molecule hauv kev sib hloov ua tiav (360◦). Yog li, ATP synthase tsim los yog hydrolyzes peb ATP molecules percycle. Qhov kev sib koom ua ke no yog qhov kev tshwm sim molecular ntawm "Splendid Molecular Machine" txhawb nqa los ntawm kev sib koom ua ke hloov pauv mechanism ntawm ()3 qauv [21]. Tseeb, qhov chaw catalytic tuaj yeem xav tias peb qhov sib txawv ntawm qhov sib txawv ntawm qhov sib txawv rau adenine nucleotide.

TP, DP, thiab E muaj peb nucleotide khi-xeev: thawj muaj ATP lossis ATP analogs hauv qhov chaw catalytic, qhov thib ob muaj ATP lossis ADP, thiab thib peb tsis muaj nucleotide khi. Qhov kev sib raug zoo rau adenine nucleotide txo qis hauv qhov tsis muaj ATP thiab tso cai rau "kaw" raws li TP, DP xeev, lossis "qhib" xeev nrog E. Cov enzyme kinetics ntawm cov chaw catalytic xav tau kev sib koom tes nucleotide nrog cov cofactor tseem ceeb Mg{{1} } [22], uas ua rau lub catalytic site asymmetry, ua qhov sib txawv affinities rau ATP [23].

Ntawm qhov tsis sib xws, tag nrho cov subunits uas txuas mus rau ATP molecule koom tes nrog Mg2+ cofactor thiab tsis raug tshuaj lom neeg hloov pauv. MgATP khi rau cov chaw uas tsis yog-catalytic muaj lub luag haujlwm tseem ceeb hauv kev tso cai rau kev tshem tawm ntawm ADP los ntawm cov chaw. Tshwj xeeb, ATP hydrolysis formsan E lub xeev loaded nrog ADP nyob rau hauv ib tug "ib nrab-kaw" conformation uas yuav inhibit lub ATPsynthase nyob rau hauv tsis muaj MgATP mus rau hauv lub non-catalytic sites [24] .Tsis ntev los no, Pinke li al. tau nthuav tawm cov qauv cryo-EM ntawm ATP synthase nrog cov cofactor thenatural Mg2+ hloov hauv cov chaw catalytic los ntawm Ca2+ [25].

ATP synthaseactivated los ntawm Ca2+ raws li ib cofactor txhawb nqa tsuas yog cov kev ua haujlwm monofunctional ntawm ATP hydrolysis, thaum ATP synthesis tsis tso cai. Nyob rau hauv-tawm subochondrial hais, thehydrolysis ntawm ATP nyob rau hauv lub xub ntiag ntawm Ca2+ txiav txim lub acridine fluorescence unquenching [26]. Hloov pauv, ATPase kev ua haujlwm yog hloov kho los ntawm ∆p [27]. Rau cov txiaj ntsig sib txawv no, Ca2+-dependent ATP hydrolysis ua ke rau H + kev ua haujlwm tau sib cav, txawm hais tias qhov kev sib hloov unidirectional catalysis tau khaws cia [28].

Txawm li cas los xij, lub luag haujlwm pathophysiological ntawm Ca2+- txhawb nqa ATP hydrolysis yuav tsum tsis raug tshawb xyuas hauv cov haujlwm ntawm ATP synthase (un) txuas rau H + kev hloov pauv, tab sis nyob rau hauv induction ntawm conformationalchanges uas ua rau tsim mPTP [29]. Qhov tseem ceeb, tus qauv zoo li qub peripheral mus rau lub hauv paus rotor, uas nthuav dav tag nrho ATP synthase ntev, ua raws li stator los tiv thaiv ( ) 3 rotation torque los ntawm lub hauv paus stalk.

Lub peripheral stalk (PS) ua kom lub zog hloov pauv ntawm cov enzyme nrog rau hydrophilic F1 domain enzyme kev ua ke rau H + kev hloov chaw hauv hydrophobicFO domain [22,30]. PS yog tsim los ntawm hydrophilic thiab hydrophobic subunits. Theformers yog oligomycin rhiab heev-conferring protein (OSCP), F6, soluble feem ntawm b, thiab d subunit khi rau ( ) 3 hexameric qauv ntawm lub npe F1, whereas thehydrophobic feem ntawm b thiab A6L subunits tsim ib feem nyob rau hauv lub IMM. PS (Daim duab 1).

Txawm li cas los xij, kev tiv thaiv ntawm kev sib hloov ntawm lub globular catalytic qauv ntawm F1 domain nrog lub rotor yog tso cai los ntawm kev siv lub elastic feature ntawm PS.Qhov interdomain pob khawm txav ntawm OSCP tuaj yeem pab txhawb kev hloov pauv ntawm F1 thiab FO [31].

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