Mitochondrial Kinase PINK1 hauv Mob raum Ntshav Qab Zib
Mar 07, 2023
Chunling Huang *, Ji Bian, Qinghua Cao, Xin-Ming Chen thiab Carol A. Pollock *
Abstract: Mitochondria yog cov organelles tseem ceeb uas ua lub luag haujlwm tseem ceeb hauv cellular metabolism, ciaj sia taus, thiab homeostasis. Mitochondrial dysfunction tau cuam tshuam rau hauv pathogenesis ntawm tus kab mob raum mob ntshav qab zib. Kev ua haujlwm ntawm mitochondria yog tswj hwm los ntawm ntau lub mitochondrial protein kinases, suav nrog phosphatase thiab tensin homolog (PTEN)-induced kinase 1 (PINK1). Kev tsom xam ntawm PINK1 kev tshawb fawb tau nyob rau hauv cov kab mob neuronal. Cov kev tshawb fawb tsis ntev los no tau qhia txog qhov sib txuas ntawm PINK1 thiab ntau yam kab mob xws li kab mob raum. Qhov kev tshuaj xyuas no yuav muab cov ntsiab lus luv luv ntawm PINK1 thiab nws cov kev cai ntawm mitochondrial muaj nuj nqi hauv kev noj qab haus huv thiab kab mob. Lub luag haujlwm physiological ntawm PINK1 nyob rau hauv cov hlwb loj koom nrog hauv cov kab mob ntshav qab zib hauv lub raum nrog rau cov cell tubular thiab podocytes kuj tseem yuav raug sau tseg. Sib sau ua ke, cov kev tshawb fawb no tau qhia tias kev tsom mus rau PINK1 tuaj yeem muab txoj hauv kev zoo rau kev kho mob raum mob ntshav qab zib.
Cistanche txiv neej cov txiaj ntsig
Nyem qhov no mus saib Cistanche deserticola raum tonic khoom
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Ntsiab lus: PINK1; mob ntshav qab zib raum; mitochondria; mitochondria zoo tswj; mitophagy
1, Taw qhia
Mitochondria, lub zog tsim hluav taws xob ntawm lub xov tooj ntawm tes, ua ntau yam ntawm tes ua haujlwm [1]. Kev saib xyuas ntawm mitochondrial muaj nuj nqi thiab kev hloov pauv yog qhov tseem ceeb rau cellular metabolism, ciaj sia taus, thiab homeostasis. Mitochondrial puas thiab dysregulation ntawm turnover ua rau metabolic dysfunction, oxidative kev nyuaj siab, o, thiab cell tuag, tag nrho cov koom nyob rau hauv lub pathogenesis ntawm mob raum kab mob (DKD) [2]. Yog li ntawd, mitochondrial dysfunction tau raug lees paub tias yog ib qho tseem ceeb rau kev loj hlob thiab kev loj hlob ntawm cov kab mob raum mob ntshav qab zib [3]. Kev khaws cia ntawm mitochondrial homeostasis yuav theoretically tiv thaiv lub raum puas thiab tswj lub raum ua haujlwm. Cov kev tshawb fawb tau pom tias kev ua haujlwm mitochondrial feem ntau yog tswj hwm los ntawm mitochondrial protein kinases [4]. Ua kom cov mitochondrial protein kinases tau tshwm sim los ua ib qho tseem ceeb molecular mechanism kho cov lus teb mitochondrial rau metabolic stresses hauv DKD. Cov phosphatase thiab tensin homolog (PTEN)-induced kinase 1 (PINK1) tau txais kev saib xyuas raws li ib qho tseem ceeb mitochondria-targeted kinase. Tsis ntev tom qab PINK1 tau raug txheeb xyuas tias yog Parkinson tus kab mob sib txuas nrog cov noob hauv xyoo 2004, kev tshawb fawb tsom mus rau lub luag haujlwm lom neeg ntawm PINK1 feem ntau cuam tshuam txog cov kab mob neuronal [5]. Cov kev tshawb fawb tsis ntev los no tau pom tias muaj kev sib raug zoo ntawm PINK1 thiab ntau yam kab mob xws li mob qog noj ntshav, ntshav qab zib, thiab kab mob raum [6]. Qhov kev tshuaj xyuas no yuav muab cov ntsiab lus luv luv ntawm PINK1 thiab tshawb nrhiav nws txoj haujlwm ntawm tes hauv kev noj qab haus huv thiab puas mitochondria nrog rau nws lub luag haujlwm ntawm lub raum hlwb feem ntau koom nrog hauv kev pib thiab kev loj hlob ntawm DKD.
Cistanche extract hmoov
(Kev tshawb fawb pharmacological niaj hnub,Cistanche deserticolatuaj yeem ua rau cov tshuaj hormones pituitary-adrenocortical,txhim kho lub cev tsis muaj zog thiab txhim kho lub peev xwm phagocytic ntawm mononuclear macrophages. Nws muaj lub luag haujlwm ntawm tonifying lub raum thiab txhawb lub yang thiab tuaj yeem tiv taus txias, hypoxia, thiab qaug zog. Cistanche deserticola kuj muaj kev ua haujlwm ntawm kev tswj hwm endocrine thiab tiv thaiv lub raum ua haujlwm.
Cistanche deserticola mamuaj qee yam cuam tshuam rau cov ntsiab lus ntawm neurotransmitters thiabtuaj yeem txhim kho kev txawj ntse, kev nco, thiab kev sib deev ua haujlwm ntawm nas; Nws kuj muaj kev ua haujlwm ntawm kev txhawb nqa qhov quav, txhim kho kev ua haujlwm ntawm plab hnyuv, thiab muaj qee yam kev tiv thaiv lub siab; Nws kuj muaj qhov pom tseeb los tiv thaiv kev laus, tiv thaiv dawb radical puas tsuaj, dawb radical scavenging teebmeem, thiab tuaj yeem ua rau lub neej ntev; Nws kuj muaj cov haujlwm ntawm kev txo cov ntshav siab, txhawb kev loj hlob thiab kev loj hlob, thiab txhawb kev tiv thaiv kab mob hauv lub cev.）
2. Txheej txheem cej luam ntawm PINK1
2.1. Kev nthuav qhia thiab yam ntxwv ntawm PINK1
Lub mitochondrial kinase PINK1 tau txheeb xyuas thiab muaj npe nyob rau xyoo 2001 thaum nws tau lees paub tias yog raug ntxias los ntawm cov qog qog nqaij hlav PTEN hauv cov qog nqaij hlav endometrial [7]. PINK1, encoded los ntawm PARK6 noob, muaj yim exons, uas encode ib 581 amino acid (aa) protein nrog N-terminal mitochondrial targeting sequences (MTS), transmembrane domain (TMD), ua raws li serine / threonine kinase domain, thiab C-terminal putatively regulatory domain. Zoo li feem ntau mitochondrial proteins, PINK1 polypeptide yog encoded nyob rau hauv lub nucleus, synthesized ntawm cytosolic ribosomes raws li ib tug precursor, thiab thauj mus rau hauv mitochondria.
Raws li kev noj qab haus huv thiab nyob ruaj khov, PINK1 raug xa mus rau hauv mitochondria los ntawm kev them nyiaj zoo N-terminal MTS, ntawm txoj hauv kev ua ntu zus, uas yog koom nrog hauv kev tsom mus rau feem ntau matrix-localized proteins thiab qee cov mitochondrial inner membrane (MIM) - thiab intra-membrane chaw (IMS)-localized proteins [8]. Los ntawm qhov no cleavable N-terminal teeb liab ib ntus, cov precursor proteins yog thawj zaug lees paub los ntawm cytosol-exposed Tom receptors (Tom20, Tom22, Tom70) ntawm lub mitochondrial txheej membrane (MOM), coj mus rau hauv lub Tom40 channel, thiab pauv mus rau Tim23 complex nyob rau hauv lub MIM. Cov proteins ncav cuag lub mitochondrial puab daim nyias nyias los ntawm Tim23 channel, nyob ntawm seb mitochondrial transmembrane muaj peev xwm, qhov sib lawv liag translocase-sociated lub cev muaj zog (PAM), thiab ATP-nyob ntawm mitochondrial tshav kub-shock protein 70 [8].
Ib qho ntawm cov txheej xwm proteolytic cleavage tau koom nrog hauv PINK1 cov txheej txheem importing. Whilst nws spans lub mitochondrial puab membrane, N-terminal MTS sau mus txog lub matrix thiab yog cleaved los ntawm lub matrix-localized protease (MPP), uas ua rau ib tug 60-kDa intermediate daim ntawv (cleavage ntawm aa 34 thiab 35) [ 9]. Lub mitochondrial inner membrane protease, presenilin-associated rhomboid-zoo li protease (PARL), ces catalyzes thib ob cleavage ntawm amino acids Ala103 thiab Phe104 nyob rau hauv lub PINK1 ib theem zuj zus, tsim lub 52-kDa ua PINK1 [10–13]. Tsis tas li ntawd, ob qho lwm yam ATP-dependent mitochondrial proteases, matrix-AAA (m-AAA) thiab caseinolytic mitochondrial matrix peptidase tau tshaj tawm tias koom nrog PINK1 cleavage [9]. Txawm li cas los xij, lub luag haujlwm tseeb thiab qhov tseeb ntawm qhov chaw ntawm cov proteases yuav tsum tau qhia meej. Tom qab cleavage los ntawm qhov sib txawv proteases, cov paub tab thiab 52-kDa ua tiav PINK1 raug tso tawm rau hauv cytosol, qhov uas nws yuav ruaj khov los ntawm kev tsim cov complexes nrog cov protein sib txawv los yog degraded los ntawm proteasomes [14]. Cov proteins uas cuam tshuam nrog PINK1 thiab tswj nws txoj kev ruaj ntseg muaj xws li cov proteins xws li Hsp90/Cdc37, cov tswv cuab ntawm Bcl-2-cov protein sib txuas xws li BAG2, BAG5, thiab BAG6 [15–18] nrog rau cov khoom ntawm sorting thiab assembling machinery (Sam50) [19]. Kev degradation ntawm 52-kDa PINK1 feem ntau yog tswj hwm los ntawm txoj kev ubiquitin/proteasome los ntawm kev ubiquitination ntawm Lys-137 (K137), tab sis tsis yog los ntawm N-kawg txoj cai mechanism, raws li yav dhau los tau npaj [20,21 ]. Tsis ntev los no, ib txoj hauv kev tshiab proteasome degradation rau PINK1 tau raug txheeb xyuas, uas tso siab rau kev cuam tshuam nrog endoplasmic reticulum-sociated degradation machinery, suav nrog valosin-muaj protein (VCP), E3 ligases gp78, thiab HRD [22]. Raws li qhov tshwm sim, hauv kev noj qab haus huv mitochondria, PINK1 yog tsim los, cleaved, thiab degraded, uas ua rau qis qis ntawm PINK1 hauv lub xeev tsis muaj zog thiab tiv thaiv kev ua kom PINK1 kinase.
2.2. Kev ua haujlwm ntawm PINK1 hauv Mitochondria
PINK1 tau nthuav tawm thoob plaws hauv lub cev thiab nyob hauv ob qho tib si mitochondria thiab cytosol. Raws li ib qho ntawm ntau haiv neeg cov protein kinases, PINK1 tswj ntau yam ntawm mitochondrial thiab cytosolic txoj hauv kev los ntawm ntau yam substrates nyob ntawm nws cov subcellular localization thiab kev noj qab haus huv ntawm mitochondria (Daim duab 1)
Daim duab 1.Kev ua haujlwm ntawm PINK1 hauv kev noj qab haus huv thiab puas mitochondria. Hauv kev noj qab haus huv mitochondria, PINK1 tswj hwm apoptosis, mitochondrial ua pa, cell loj hlob lossis sib txawv, thiab autophagy / mitophagy. Hauv kev puas tsuaj mitochondrial, PINK1 ua lub luag haujlwm tseem ceeb hauv autophagy / mitophagy, mitochondrial fission thiab fusion, mitochondrial biogenesis, mitochondrial motility, thiab mitochondria-derived vesicles (MDVs) nrog rau calcium signaling thiab apoptosis.
2.2.1. Lub luag haujlwm ntawm PINK1 hauv Kev Noj Qab Haus Huv Mitochondria
Hauv kev noj qab haus huv mitochondria, cov kev tshawb fawb tsis ntev los no tau qhia tias N-terminal cleaved PINK1 tso rau hauv cytosol muaj cov haujlwm sib txawv ntawm tes ua haujlwm los ntawm cov dej sib txawv hauv qab [14]. N-terminally truncated, cytosolic PINK1 tiv thaiv oxidative stress-induced apoptosis los ntawm phosphorylating lub qog necrosis factor receptor-associated protein 1 (TRAP1) / heat shock protein 75 (Hsp75), ib tug tswv cuab ntawm HSP90 tsev neeg ntawm mitochondrial chaperone [23] thiab serine protease high-temperature-requirement protein A2 (HtrA2) [24]. PINK1 tswj mitochondrial ua pa los ntawm phosphorylation ntawm complex I subunit, NADH dehydrogenase ubiquinone 1 alpha subcomplex 10 (NdufA10) [25]. Ntxiv mus, cytosolic PINK1 txhawb nqa kev loj hlob ntawm neuronal thiab kev sib txawv los ntawm kev ua kom lub hom phiaj ntawm cov tsiaj nyeg ntawm rapamycin complex 2 (mTORC2) / Akt [26] nrog rau phosphorylation ntawm PKA / p47 kev taw qhia txoj hauv kev [27]. Interestingly, cytosolic PINK1 tau tshaj tawm los txhawm rau txo qis autophagy / mitophagy los ntawm kev hloov pauv ntawm mitochondrial fission [28] thiab PKA-mediated LC3 phosphorylation [29]. Los ntawm kev khi ncaj qha rau cytosolic Parkin, cytosolic PINK1 tiv thaiv kev hloov pauv ntawm Parkin mus rau sab nrauv mitochondria thiab txo qis tom qab valinomycin-dependent mitophagy [30]. Xwb, ua ke nrog Parkin thiab cytosolic protein DJ-1 (PPD), tsim ib qho kev ua haujlwm E3 ligase complex, PINK1 txhawb nqa ubiquitination thiab proteasomal degradation ntawm misfolded Parkin substrates suav nrog Parkin nws tus kheej thiab synphilin-1 los tiv thaiv kev pib ntawm mitophagy [31]. Hauv qhov sib piv, txoj kev tshawb fawb los ntawm Gao et al. tau txheeb xyuas daim ntawv luv luv ntawm cytosolic PINK1 raws li tus neeg nruab nrab loj ntawm kev tsim aggresome thaum lub sij hawm proteasomal kev nyuaj siab. Lub phosphorylation ntawm ubiquitin-binding protein SQSTM1 / P62 (sequestosome 1) ntawm Ser28 los ntawm PINK1 yog qhov yuav tsum tau ua kom muaj txiaj ntsig zoo, qhia txog lub luag haujlwm tseem ceeb ntawm PINK1 hauv autophagic degradation [32].
2.2.2. Ua kom PINK1 hauv Damaged Mitochondria
Hauv kev teb rau kev puas tsuaj mitochondrial, kev poob ntawm mitochondrial membrane muaj peev xwm ua rau muaj kev ruaj khov ntawm PINK1 ntawm mitochondrial txheej membrane. Qhov sib sau tag nrho-ntev PINK1 ntawm MOM tau ua kom dim, uas tom qab ntawd ua rau autophosphorylation thiab ua kom cov kinase [33,34]. Ua kom PINK1 ua haujlwm raws li qhov tseem ceeb mitochondrial zoo tswj cov protein hauv kev tswj hwm mitochondrial homeostasis nrog rau mitophagy, fission, thiab fusion nrog rau biogenesis los ntawm kev nrhiav neeg ua haujlwm thiab phosphorylation ntawm ntau lub substrates [6].
Mitophagy yog qhov kev xaiv degradation ntawm mitochondria tsis zoo los ntawm autophagy tom qab kev puas tsuaj lossis kev ntxhov siab, uas ua lub luag haujlwm tseem ceeb hauv kev tswj cov mitochondrial. Thaum lub sij hawm tus txheej txheem ntawm mitophagy, activated PINK1 ua rau ib tug cascade ntawm cov txheej xwm los ntawm txawv substrates. Ua ntej, PINK1 tau qhib los ntawm autophosphorylation ntawm Ser228, Ser402, Thr257, thiab Thr313, uas thawj ob cuam tshuam rau Parkin thiab tom qab ubiquitin phosphorylation [33]. Parkin, ib qho E3 Ubiquitin ligase, yog ib qho zoo tshaj plaws-tus cwj pwm qis qis qis ntawm PINK1, thiab PINK1 / Parkin txoj kev raug lees paub tias yog tus neeg kho mob loj ntawm mitophagy. Stabilized PINK1 phosphorylates Parkin ntawm Ser65 residue ntawm nws cov N-terminal ubiquitin-zoo li sau thiab induces recruitment ntawm Parkin rau puas mitochondria [35]. PINK1 kuj phosphorylates ubiquitin ntawm residue Ser65, uas ua rau kom muaj kev ua haujlwm ntawm Parkin E3 ligase [36]. Ua ke, cov kev ua no muab lub voj voog tawm tswv yim zoo los qhib E3 ligase kev ua ntawm Parkin, tso cai rau nws mus rau ubiquitinate proteins nyob ntawm MOM interface thiab pib mitophagy. Tsis tas li ntawd, PINK1 kuj tseem siv ntau lwm yam ubiquitin E3 ligases los kho Parkin-ywj siab mitophagy, uas suav nrog Siah E3 Ubiquitin Protein Ligase 1 (SIAH1) [37], Ariadne RBR E3 Ubiquitin Protein Ligase 1 (ARIH1) [38], thiab ligase 1 (MUL1) [39]. Phosphorylated PINK1 nrhiav thiab ua rau Parkin lossis lwm yam E3 ligases rau ubiquitinate mitochondrial proteins, uas tom qab ntawd txhawb kev nrhiav neeg ua haujlwm ntawm mitophagy adapter proteins (ie, nuclear dot protein 52 thiab optineurin) thiab pab tshem tawm cov kev puas tsuaj mitochondria los ntawm ubiquitin-mediated mitoph.
PINK1 tau pom tias muaj kev cuam tshuam nrog cov khoom ntawm mitochondrial fission thiab fusion machinery, xav txog nws lub luag haujlwm hauv mitochondrial dynamics [41]. Mitochondrial fission yog xav tau rau mitophagy los ntawm kev tsim cov mitochondrial me me kom tau engulfed los ntawm autophagosome. Dynamin-related protein 1 (Drp1) yog tus tswj hwm loj ntawm mitochondrial fission. PINK1 txhawb nqa Drp1-dependent mitochondrial fission los ntawm kev nrhiav neeg ua haujlwm ntawm Drp1 rau mitochondria ua ke nrog Parkin thaum lub sij hawm mitophagy [42]. Tsis tas li ntawd, PINK1 ua raws li lub zog fission activator los txhawb mitochondria fission los ntawm kev tswj hwm kev ua haujlwm ntawm Drp1 los ntawm A-kinase anchoring protein 1 (AKAP1)- protein kinase A (PKA) axis, uas yog ywj siab ntawm Parkin kev ua thiab calcium. Ib txoj kev tshawb fawb tsis ntev los no tau lees paub tias PINK1 tuaj yeem ncaj qha phosphorylate Drp1 ntawm Ser616 qhov chaw, muab cov txheej txheem tshiab rau PINK1 hauv kev tswj hwm mitochondrial fission [43,44]. Mitochondrial fusion yog qhov tseem ceeb hauv kev tswj hwm cov neeg noj qab haus huv mitochondrial los ntawm kev faib tawm cov ntsiab lus mitochondrial los tiv thaiv kev sib sau ntawm cov khoom puas. Lub mitochondrial fusion ntawm MOM yog tswj los ntawm mitofusin 1 (Mfn1) thiab mitofusin 2 (Mfn2). Mfn1 thiab Mfn2 tau raug txheeb xyuas tias yog qhov tshiab ubiquitination substrates thaum lub sij hawm mitophagy, uas, raws li tau hais los saum no, yog nyob ntawm PINK1 thiab Parkin [45]. PINK1 kho cov ubiquitination thiab proteasomal degradation ntawm Mfn1/2 nyob rau hauv ib tug Parkin thiab p97-raws li nyob rau hauv inhibit qhov refusion ntawm puas mitochondria los ntawm noj qab nyob zoo mitochondria thiab pab txhawb kev tshem tawm ntawm impaired mitochondria [46]. Rocha et al. tau txheeb xyuas thiab siv tau peb qhov chaw PINK1 phosphorylation ntawm tib neeg Mfn2 (Ser378, Thr111, Ser442) siv cov spectrometry loj [47]. Phosphorylation ntawm Mfn2 los ntawm PINK1 ntawm Ser378 modulates mitochondrial fusion, whilst phosphorylation ntawm Mfn2 los ntawm PINK1 ntawm Thr 111 thiab Ser 442 ua hauj lwm raws li mitochondrial receptors rau Parkin los txhawb mitophagy [47,48]. Txawm li cas los xij, Mfn2 kuj ua raws li mitochondria-endoplasmic reticulum (ER) tether los ua kom nws cov nyhuv antagonistic ntawm mitophagy [49], uas yog ywj pheej ntawm mitochondrial fusion. Lub phosphor ubiquitination thiab degradation ntawm Mfn2 kho los ntawm PINK1 / Parkin, cuam tshuam mitochondria-ER kev sib cuag thiab tso tawm ER los ntawm mitochondria los tsav mitophagy, qhia lub luag haujlwm tseem ceeb ntawm ER-mitochondria hu rau mitophagy [49].
Cistanche lub cev tsim
Mitochondrial biogenesis, txheej txheem los nce mitochondrial loj, yog ib feem tseem ceeb ntawm mitochondrial network. PINK1 kuj tau pom tias muaj kev koom tes hauv mitochondrial biogenesis. PINK1 tuaj yeem cuam tshuam ncaj qha rau mitochondrial DNA synthesis, uas yog tsim nyog rau mitochondrial biogenesis [50]. PINK1 kinase kev ua haujlwm yuav tsum tau ua rau Parkin-mediated ubiquitination thiab degradation ntawm Parkin interacting substrate (PARIS), KRAB thiab zinc ntiv tes protein, los ntawm phosphorylation ncaj qha ntawm serine residues 322 thiab 613 [51]. PINK1 depletion ua rau cov tsub zuj zuj ntawm PARIS thiab kev tsim txom ntawm transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1), tus tswv tswj ntawm mitochondrial biogenesis, yog li inhibiting bio mitochondrial. 51] ib. Lub luag haujlwm ntawm PINK1 hauv mitochondrial biogenesis ntawm PARIS/PGC-1 axis tau lees paub ntxiv hauv Drosophila qauv [52].
Muaj ntau ntau ntxiv PINK1 substrates tau tshaj tawm tias tau koom nrog hauv kev tswj hwm mitochondrial. Miro, mitochondrial Rho GTPase ntawm mitochondrial txheej membrane, yog phosphorylated los ntawm PINK1 tsis yog ntawm S156 nkaus xwb tab sis kuj ntawm T298/299. Cov xwm txheej ntawm Miro phosphorylation tswj mitochondrial motility los ntawm kev hloov pauv ntawm Parkin qib. PINK1- nyob ntawm phosphorylation ntawm Miro ntawm Ser156 nrhiav Parkin mus rau mitochondria thiab ua rau Miro proteasomal degradation thiab inhibition ntawm mitochondrial motility, thaum phosphorylation ntawm Miro ntawm T298/T299 exerts qhov opposite nyhuv [53,54]. Substrate-driven activation los ntawm Miro yuav ua rau lwm hom kev ua kom Parkin ntxiv rau PINK1 phosphorylation ntawm ubiquitin lossis Parkin [53]. Ib txoj kev tshawb nrhiav phosphoproteomic tau qhia tias Rab GTPases suav nrog Rab8A, Rab8B, thiab Rab13 tau raug txheeb xyuas tias yog lub hom phiaj qis qis ntawm PINK1. Ua kom PINK1 tsis ncaj qha phosphorylates Rab GTPases Rab8A ntawm serine 111, uas tsis zoo tswj cov leucine-nplua nuj rov kinase 2 (LRRK2)-mediated phosphorylation ntawm Rab8A ntawm Thr72 [55,56]. Inhibition ntawm LRRK2 kinase kev ua ub no rov qab kho PINK tsis zoo1- nyob ntawm mitophagy hauv Parkinson tus kab mob, qhia txog kev sib txuas ntawm PINK1 thiab LRRK2 [56,57]. Nws tsim nyog sau cia tias PINK1 tseem koom nrog kev tsim cov mitochondria-derived vesicles (MDVs), uas yog lwm txoj hauv kev rau mitochondria degradation thiab txawv ntawm canonical mitophagy [58]. Cov kev ntxhov siab-induced PINK1/Parkin-dependent MDVs xaiv thauj oxidized los yog puas mitochondrial cov ntsiab lus mus rau lig endosome/lysosome rau degradation, uas yog kho los ntawm syntaxin-17 [58].
Ntxiv nrog rau nws lub luag haujlwm hauv kev tswj hwm mitochondrial, PINK1 ua lub luag haujlwm tseem ceeb hauv lwm cov haujlwm ntawm tes. Piv txwv li, PINK1 tuaj yeem txhawb nqa autophagy los ntawm kev sib cuam tshuam ncaj qha nrog Beclin1, ib qho tseem ceeb tshaj plaws pro-autophagic protein [59]. PINK1 kinase kev ua haujlwm yuav tsum muaj rau mitochondrial Ca2 ntxiv rau kev tswj hwm. PINK1 ncaj qha tswj mitochondrial calcium efflux ntawm kev hloov pauv ntawm mitochondrial Na plus / Ca2 plus exchanger [60]. Ib txoj kev tshawb fawb loj spectrometry-based interactomics tshuaj ntsuam xyuas tau txheeb xyuas cov leucine zipper-EF-tes uas muaj transmembrane protein 1 (LETM1), mitochondrial inner membrane protein, raws li lub peev xwm PINK1 interacting proteins [61]. PINK1 phosphorylates LETM1 ntawm Thr192 los kho mitochondrial Ca2 ntxiv rau kev thauj mus los [61]. Ntxiv mus, PINK1 tuaj yeem tiv thaiv carbonyl cyanide m-chlorophenyl hydrazine (CCCP)-induced apoptotic cell tuag los ntawm phosphorylation ntawm anti-apoptotic protein Bcl-xL ntawm serine 62, ib tug tswv cuab ntawm Bcl -2 tsev neeg [62] .
Sib sau ua ke, nws pom tias PINK1 tswj hwm mitochondrial zoo tswj kom muaj zog homeostasis nrog rau mitophagy (xws li Parkin, ubiquitin, E3 ligases), mitochondrial dynamics (ntawm Mfn1 / Mfn2, Drp1), mitochondrial biogenesis (via motochondria), ) thiab MDVs (ntawm syntaxin-17) nrog rau autophagy machinery (ntawm Beclin 1), calcium signaling (ntawm Na plus / Ca2 plus exchanger, LETM1), thiab apoptosis (ntawm Bcl-xL).
Li no, qhov sib txawv isoforms ntawm PINK1 nyob rau hauv cov sib txawv subcellular pas dej ua ke, uas ua hauj lwm multifunctional ua si los ntawm ntau yam downstream substrates (Table 1). Kev txheeb xyuas ntxiv ntawm cov substrates ntawm PINK1 yuav muab kev nkag siab zoo ntawm nws cov haujlwm ntawm tes.
MOM, mitochondrial txheej membrane, IMS, intermembrane chaw, MIM, mitochondrial puab membrane.
3. Lub luag haujlwm Physiological ntawm PINK1 hauv DKD
Nws tau paub ntau ntxiv tias mitochondrial dysfunction tau cuam tshuam rau hauv pathogenesis ntawm DKD. PINK1 yog tam sim no nyob rau hauv cov hlwb loj koom nrog hauv kev loj hlob ntawm DKD, suav nrog cov cell tubular thiab podocytes (Table 2). Yog li, kev tsom mus rau mitochondria kom rov qab ua haujlwm mitochondrial tuaj yeem muab cov kev kho mob zoo rau kev kho DKD.
3.1. PINK1 hauv Tubular Epithelial Cells
Proximal tubule epithelial hlwb, hom cell uas tseem ceeb tshaj plaws nyob rau hauv lub raum cortex, ua lub luag haujlwm hauv reabsorption ntawm kua, qabzib, amino acids, thiab lwm yam khoom lim los ntawm glomerulus. Proximal tubule hlwb yog nplua nuj nyob rau hauv mitochondria nrog siab zog thov thiab yog li ntawd, yooj yim rau mitochondrial dysfunction [72]. Cov pov thawj loj hlob qhia tau hais tias kev raug mob ntawm tubule ze ze ze rau lub raum kev ua haujlwm txawv txav thiab tau txais kev lees paub ntau ntxiv tias yog tus kws kho mob tseem ceeb hauv kev pib thiab kev loj hlob ntawm DKD [73,74].
Lub luag haujlwm ntawm PINK1 nyob rau hauv tubular hlwb nyob rau hauv cov mob ntshav qab zib tau tshwm sim, nrog cov pov thawj tsis ntev los no qhia tias PINK1-kev tswj hwm mitochondrial zoo, tshwj xeeb tshaj yog dysregulated mitophagy, yog koom nrog hauv kev raug mob ntshav qab zib. Zhan et al. qhia tias hyperglycemia inhibited qhov kev qhia ntawm PINK1, punctate LC3 (microtubule-associated protein 1A/1B-light chain 3), thiab mitochondrial profusion protein Mfn2, tab sis nce kev qhia ntawm mitochondrial fission protein Drp1 thiab Fis1 nyob rau hauv lub raum proximal tubular hlwb nyob rau hauv siab. Cov mob ntshav qab zib thiab hauv streptozotocin (STZ)-induced type 1 diabetes nas [63]. Cov kev hloov pauv txawv txav tau qhia tias muaj kev cuam tshuam mitochondrial zoo tswj nrog nce mitochondrial fragmentation thiab txo mitophagy, uas tau txo qis los ntawm inhibition ntawm Myo-inositol oxygenase (MIOX), tubular-specific enzyme, nrog D-glucarate [63]. Ib yam li ntawd, PINK1- nruab nrab mitophagy kuj tau inhibited nyob rau hauv tubular hlwb ntawm 24-lub lim tiam-laus db/db nas, hom 2 mob ntshav qab zib nas qauv. Qhov tsis zoo mitophagy hauv cov nas mob ntshav qab zib tau tshwm sim los ntawm kev txo qis PINK1 transcription thiab Parkin phosphorylation, uas tau nrog los ntawm kev tsis txaus ntseeg mitochondrial dynamics nrog Drp1 activation thiab Mfn2 suppression. Kev kho mob MitoQ txo qis raum raug mob thiab tubulointerstitial fibrosis hauv DKD los ntawm kev kho dua tshiab ntawm mitophagy hauv cov ntshav qab zib ob lub raum, uas yog kho los ntawm Nrf2/PINK txoj kev [64]. Hauv qhov sib piv, qhov nthuav qhia ntau ntxiv ntawm PINK1 tau tshaj tawm hauv plaub lub lis piam STZ-vim cov nas mob ntshav qab zib ua ke nrog kev qhia ntau ntxiv ntawm Drp1. Mob ntshav qab zib ua rau lub raum mitochondrial tsis ua haujlwm tuaj yeem cuam tshuam nrog kev poob ntawm lub raum calpain 10, mitochondrial thiab cytosolic Ca2 ntxiv - tswj cysteine protease [65]. Kev tshawb fawb los ntawm Liu et al. pom tau hais tias PINK1/Parkin-mediated mitophagy, raws li muaj pov thawj los ntawm qib siab ntawm PINK1 thiab Parkin, tau qhib rau hauv ob lub raum ntawm 21-lub lim tiam db/db nas [66]. Cov kev tshawb pom no tau lees paub ntxiv los ntawm tib pab pawg hauv lawv txoj kev tshawb fawb tsis ntev los no [67]. Cov kws sau ntawv tau sib cav hais tias qhov sib txawv ntawm qhov qhia theem ntawm PINK1 thiab lub xeev ntawm mitophagy nyob rau hauv DKD yog feem ntau vim yog kev xaiv tsiaj txhu, lub voj voog ntawm kev sim, thiab cov ntshav qabzib txij li theem ntawm mitophagy hloov nrog rau kev loj hlob ntawm DKD [ 67] ib. Yog li no, kev tshawb nrhiav ntxiv siv PINK1 gene knockout tsiaj qauv yog xav tau kom nkag siab zoo dua lub luag haujlwm ntawm PINK1 hauv DKD.
3.2. PINK1 hauv Podocytes
Podocytes yog cov hlwb tshwj xeeb uas muaj lub luag haujlwm tseem ceeb hauv kev tswj cov glomerular filtration barrier. Podocyte puas tsuaj los yog ua haujlwm tsis zoo ua rau muaj proteinuria, uas yog ib qho ntawm cov yam ntxwv ntxov tshaj plaws tau pom hauv DKD [75]. Txawm hais tias cellular mitochondrial cov ntsiab lus hauv podocytes qis dua hauv tubular epithelial hlwb, podocyte mitochondrial dysfunction tshwm sim los ntawm kev puas tsuaj mitophagy koom nrog hauv cov kab mob glomerular lesions, qhia qhov tseem ceeb ntawm podocytes hauv DKD [76]. Yog li, kev tswj hwm homeostasis ntawm podocyte hlwb yog qhov tseem ceeb rau kev khaws cia ntawm glomerular muaj nuj nqi.
Incubation ntawm nas podocytes nyob rau hauv siab qabzib (HG) nruab nrab rau 72 h inhibited mitophagy kev ua ub no raws li pov thawj los ntawm kev txo qis ntawm PINK1, uas tau nrog los ntawm kev txo qis transcriptional kev ua si ntawm forkhead-box chav kawm O1 (FoxO1) thiab nce podocyte apoptosis [68]. Kev nthuav tawm ntau dhau ntawm FoxO1 txo qis podocyte apoptosis thiab txo qis podocyte cell puas los ntawm kev txhim kho ntawm PINK1 qhia hauv HG-kho podocytes thiab glomeruli ntawm cov nas mob ntshav qab zib, qhia txog kev sib cuam tshuam ntawm PINK1 thiab FoxO1 [68]. Tib pab pawg tau lees paub ntxiv tias hyperglycemia inhibited mitophagy hauv podocytes, uas ua rau muaj qhov tsis zoo ntawm mitochondrial morphology thiab mitochondrial dysfunction nyob rau hauv kab lis kev cai nas podocyte hlwb (CIMPs) thiab STZ-induced diabetic nas [69]. Los ntawm kev kawm txog kev txhawb nqa kev ua ub no, nws tau lees paub tias PINK1 yog lub hom phiaj ncaj qha ntawm FoxO1, uas feem ntau ua los ntawm PINK1-binding site [69]. Kev tswj hwm ntawm FoxO1 tiv thaiv cov piam thaj siab ua rau mitochondrial dysfunction thiab podocyte raug mob hauv ob qho tib si hauv vitro thiab hauv vivo mob ntshav qab zib qauv, uas tau kho los ntawm kev ua kom PINK1 / Parkin-dependent mitophagy [69]. Zhou thiab cov npoj yaig kuj tau tshaj tawm qhov kev txo qis hauv qhov kev qhia ntawm PINK1, PARK2, PGC-1 , thiab Sirt1, qhia tias mitophagy thiab mitochondrial biogenesis puas tsuaj hauv DKD [70]. Kev tswj hwm ntawm progranulin (PGRN), uas yog secreted glycoprotein, tiv thaiv qhov kev loj hlob ntawm DKD los ntawm kev xaiv tshem tawm ntawm dysfunctional mitochondria los ntawm mitophagy thiab induction ntawm mitochondrial biogenesis kom tswj mitochondrial homeostasis hauv podocytes [70]. Mob ntshav qab zib dyslipidemia yog ib qho ntawm cov kev pheej hmoo loj rau kev loj hlob thiab kev loj hlob ntawm DKD. Interestingly, palmitic acid (PA) induced nthuav qhia ntawm PINK1 thiab Parkin nyob rau hauv podocytes, qhia tias PINK1 / Parkin-mediated mitophagy tau qhib rau hauv lipid-induced lipotoxicity, uas tau lees paub nyob rau hauv tus nas qauv ntawm HFD-vim rog rog [71]. Parkin knockdown inhibited mitophagy hauv podocytes, uas ntxiv txhim kho PA-induced mitochondrial puas, mitochondrial ntau lawm, thiab podocyte apoptosis, qhia tias PINK1 / Parkin-mediated mitophagy exerts kev tiv thaiv kev tiv thaiv hyperlipidemia hauv DKD [71].
Txawm hais tias theem ntawm PINK1 / Parkin-dependent mitophagy, raws li qhia los ntawm theem qhia ntawm PINK1, nws txawv ntawm cov qauv ntawm tes thiab tsiaj sib txawv, nws tau lees paub tias PINK1- mediated mitophagy plays lub luag haujlwm tiv thaiv hauv DKD. Yog li ntawd, kev ua kom PINK1 kev ua kom rov qab kho mitophagy yuav muaj txiaj ntsig zoo hauv DKD.
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4. Pharmacological Activation ntawm PINK1
PINK1 kinase kev ua haujlwm tuaj yeem nce ncaj qha los ntawm cov khoom siv hluav taws xob me me. ATP analog N6-furfuryl ATP (kinetin triphosphate, KTP) yog thawj zaug uas tau txheeb pom tias yog ib qho ncaj qha me me molecular activator ntawm PINK1 hauv cov hlwb, uas txhim kho PINK1- nyob ntawm phosphorylation thiab nrhiav Parkin rau depolarized mitochondria los pib PINK1- mediated mitophagy [77]. Txawm li cas los xij, KTP, ATP neo-substrate tsuas tuaj yeem qhib PINK1 thaum muaj tus neeg sawv cev mitochondria-depolarizing xws li CCCP, uas txwv nws daim ntawv thov. Tom qab ntawd, Osgerby et al. ua haujlwm lub zog ProTide phosphate prodrug thev naus laus zis los tsim cov nucleoside-raws li molecules thiab pom tias kinetin riboside (KR) thiab nws ProTide tuaj yeem txhim kho PINK1 kev ua haujlwm, uas yog ywj pheej ntawm mitochondrial depolarization [78]. Ntxiv rau hauv vivo cov kev tshawb fawb kom siv tau cov dej num ntawm cov tebchaw no tau lees paub.
Raws li PINK1 tuaj yeem qhib tau los ntawm kev poob ntawm mitochondrial membrane muaj peev xwm, lwm txoj hauv kev los ua kom tsis muaj zog kinase kev ua ntawm PINK1 tuaj yeem ua rau depolarise mitochondrial membrane peev xwm. Qhov no tuaj yeem ua tiav siv cov proton ionophore, CCCP, carbonyl cyanide-4-phenylhydrazone (FCCP), potassium uniporter valinomycin, lossis kev sib xyaw ntawm antimycin A thiab oligomycin A [79]. Txawm li cas los xij, qhov tshwm sim ntawm cellular toxicity txwv lawv hauv vivo daim ntawv thov. Tsis ntev los no, cov tshuaj anthelmintic niclosamide, tau pom zoo los ntawm FDA rau kev kho mob ntawm cov kab mob tapeworm, tau raug txheeb xyuas tias yog ib qho indirect PINK1 activator los ntawm uncoupling ntawm mitochondrial membrane tej zaum [80]. Lub peev xwm kho mob ntawm niclosamide thiab nws cov tshuaj analogues tau tshaj tawm hauv ntau yam kab mob xws li Parkinson's disease, mob qog noj ntshav, ntshav qab zib hom 2, kab mob thiab kab mob, kab mob rheumatoid, thiab kab mob sclerosis los ntawm ntau lub tswv yim xws li uncoupling ntawm oxidative phosphorylation, thiab kev hloov ntawm Wnt. / -catenin, mTORC1, STAT3, NF-κB, thiab Notch signaling pathways [81,82]. Tsis tas li ntawd, niclosamide thiab nws cov analogues tau pom tias ua rau muaj kev cuam tshuam rau hauv ntau lub raum qauv xws li unilateral ureteral obstruction, raum ischemia / reperfusion raug mob, adriamycin nephropathy, nrog rau DB / DB thiab STZ-induced type 1 mob ntshav qab zib raum raug mob [83-87. ]. Txawm hais tias nws cov txiaj ntsig zoo antifibrotic rau cov kab mob raum, lub hauv paus txheej txheem tseem tsis meej. Txog niaj hnub no, tsis muaj kev tshawb fawb qhia txog kev sib txuas ncaj qha ntawm niclosamide nrog PINK1 hauv lub raum. Amplifying PINK1 kev ua ub no thiab pib PINK1-dependent mitophagy tej zaum yuav yog ib qho tseem ceeb ntawm niclosamide hauv kev tiv thaiv kev raug mob raum, uas tsim nyog tau txais kev lees paub. Muab cov ntaub ntawv pov thawj kev nyab xeeb zoo hauv vivo, niclosamide thiab nws cov analogues yuav raug muab rov ua dua los ua cov tshuaj muaj zog los kho DKD.
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5. Cov lus xaus thiab kev pom
Kev koom tes ntawm PINK1 hauv kev tswj hwm mitochondrial muaj nuj nqi, tshwj xeeb tshaj yog PINK1-koom haum mitophagy, tau kawm ntau ntxiv hauv cov kab mob hauv lub raum. Txawm hais tias kev ua haujlwm thiab kev ua haujlwm ntawm PINK1 thiab nws cov dej ntws hauv qab tsis tau piav qhia meej, nws yog qhov tseeb tias PINK1 kinase ua lub luag haujlwm tseem ceeb hauv kev tswj hwm mitochondrial muaj nuj nqi thiab cellular homeostasis ntxiv rau kev tswj mitophagy. Tsis ntev los no, muaj ntau zuj zus ntawm kev sim tshuaj nrog ntau yam kev kho mob hom phiaj sib txawv ntawm mitochondrial dysfunction, uas muaj xws li kev hloov kho ntawm oxidative kev nyuaj siab, augmentation ntawm mitochondrial biogenesis, thiab stimulating mitochondrial dynamics [88,89]. Muab ntau lub luag haujlwm ntawm PINK1 hauv mitochondria, cov kev tshawb fawb yav tom ntej los txiav txim siab txog kev sib koom ua ke ntawm PINK1 thiab cov kev pom zoo / kev sim tshuaj tsis tu ncua xws li Sonlicromanol (KH176), Bezafibrate, thiab NAD ntxiv rau cov precursors / modulators tsim nyog tshawb nrhiav ntxiv [88,89]. Cov kev tshawb fawb no yuav tsis tsuas yog muab kev nkag siab tob dua ntawm cov txheej txheem molecular ntawm cov tshuaj tab sis kuj txheeb xyuas cov tshiab PINK1- cov neeg ua haujlwm rau kev siv tshuaj kho mob yav tom ntej. Nws tau dhau los lees paub tias qhov tsis zoo PINK1- nruab nrab mitophagy ua rau muaj kev cuam tshuam ntawm DKD. Yog li ntawd, pharmacologically activating PINK1-dependent mitophagy tej zaum yuav yog ib qho kev cog lus kho zoo rau kev kho mob ntawm DKD los ntawm kev txhim kho qhov kev tshem tawm ntawm mitochondria puas. Kev tshawb fawb yav tom ntej kom nkag siab zoo dua lub hauv paus molecular rau kev tiv thaiv lub luag haujlwm ntawm PINK1 hauv DKD yog qhov yuav tau txais txiaj ntsig zoo.
Sau Kev Pab Txhawb: CH xeeb thiab sau cov ntawv sau; JB, QC, thiab X.-MC tau tshuaj xyuas cov ntawv sau; CAP tau kho thiab tshuaj xyuas cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag: Qhov kev tshawb fawb no tau txais kev txhawb nqa los ntawm University of Sydney Ignition Seed Fund (G205251).
Institutional Review Board Statement: Tsis siv tau.
Qhia Kev Pom Zoo: Tsis siv tau.
Cov ntaub ntawv muaj nyob: Cov ntaub ntawv nthuav tawm hauv qhov kev tshawb fawb no muaj nyob rau ntawm kev thov los ntawm tus kws sau ntawv.
Kev tsis sib haum xeeb: Cov neeg sau ntawv tshaj tawm tsis muaj kev cuam tshuam ntawm kev txaus siab
Cov ntaub ntawv
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