Glucose- Thiab Tsis-Glucose-Induced Mitochondrial Dysfunction hauv Mob Ntshav Qab Zib Raum Ⅱ

3. Glucose-Induced Mitochondrial Dysfunction hauv DKD

Hauv cov cell glomerular, cov piam thaj tau coj los ntawmglucose transporters(GLUTs) los ntawm kev thauj mus los yooj yim. Cov qauv qhia ntawm txhua tus tswv cuab ntawm GLUTs yog cov xov tooj tshwj xeeb. Mesangial hlwb qhia GLUT1 thiab 4, podocytes nthuav qhia GLUT1, 4, thiab 8 thiab endothelial hlwb qhia GLUT1 [32]. Piv txwv li, tubular cells reabsorb qab zib los ntawm glomerular filtrate tsuas yog los ntawm sodium-dependent glucose cotransporters (SGLTs). Glucose reabsorbed los ntawm tubular hlwb yog dissipated thoob plaws GLUTs nyob rau hauv lub basolateral plasma membrane thiab diffuses mus rau hauv lub interstitium. Proximal tubular cells tseem tuaj yeem tsim cov piam thaj los ntawm gluconeogenesis, uas yog nce hauvmob ntshav qab zib hom 2 [33]. Hyperglycemia yog qhov tseem ceeb pathogenetic yam thiab qee qhov nruab nrab metabolites ntawmglucose metabolismkuj muaj feem cuam tshuam rau kev pabcell raug mob hauv DKD. Hauv kev sib koom ua ke kev xav uas tau muab los ntawm Brownlee thiab cov npoj yaig hauv xyoo 2000, nws tau hais tias qhov kev tsim tawm ntau dhau ntawm mtROS vim tias muaj kev nkag mus rau hauv OXPHOS tau qhib lubnuclear DNA kho enzymepoly (ADP-ribose) polymerase (PARP), ua rau txo qis kev ua haujlwm ntawm glyceraldehyde3-phosphate dehydrogenase(GAPDH) thiab tom qab sib sau ua ke ntawm cov tshuaj lom neeg nruab nrab ntawmglucose metabolism [11]. Txawm li cas los xij, tom qab kev tshawb fawb tau pom tias mitochondria tsis ua haujlwm thiab lwm yam kev ua haujlwm, ntxiv rau kev nce hauv cov substrates, ua rau muaj zog glycolysis thiab tom qab sib sau ntawm cov tshuaj lom metabolites.

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3.1. Warburg Effect

Feem ntau, cov qog nqaij hlav qog noj ntshav ua kom zoo dua glycolysis thiab cuam tshuam oxidative phosphorylation. Thaum lub sijhawm luv luv thiab rov qab hloov pauv ntawm cov txheej txheem metabolic no hu ua Crabtree effect, lub sijhawm ntev metabolic reprogramming hu ua Warburg effect [34].

Cov nyhuv Warburg yog lo lus siv los piav qhia txog kev hloov pauv ntawm OXPHOS mus rau aerobic glycolysis (nyob rau hauv uas lactate yog tsim los ua cov khoom kawg los ntawm cov piam thaj) hauv kev mob qog noj ntshav [35]. Cov kev tshawb fawb tsis ntev los no tau pom tias qhov kev hloov pauv no kuj tshwm sim hauv cov ntshav qab zib raum [9,19]. Mitochondria nyob rau hauv cov ntaub so ntswg mob ntshav qab zib yog dysfunctional, raws li tau tham saum toj no. Transscriptomic, metabolomic, thiab metabolite flux tsom xam pom tias cov piam thaj metabolism nce ntxiv thiab txo qismitochondrial muaj nuj nqinyob rau hauv lub raum cortices ntawm db/db nas [9]. Kev tshuaj xyuas metabolomics ntawm cov zis kuaj pom pom qhov txo qis ntawm 13 cov metabolites hauv cov neeg mob nrog DKD piv rau kev noj qab haus huv, 12 qhov cuam tshuam nrog mitochondrial metabolism [19]. Txawm hais tias mitochondrial dysfunction ua rau hloov mus rau glycolysis los yog nce glycolysis ua rau mitochondrial dysfunction tseem yuav tsim [36].

Pyruvate kinase yog cov enzyme uas catalyzes hloov dua siab tshiab ntawm phosphoenolpyruvate rau pyruvate, lub xeem thiab irreversible kauj ruam ntawm glycolysis. Kev txo qis pyruvate kinase M2 kev ua haujlwm tau pom tias yog qhov ua tau ntawm cov nyhuv Warburg hauv DKD los ntawm Qi thiab cov npoj yaig [37]. Lawv thawj zaug ua cov tshuaj tiv thaiv kab mob glomeruli cais tawm ntawm cov neeg mob ntshav qab zib hom 1 uas tsis tsim DKD rau ntau dua 50 xyoo (tiv thaiv) thiab cov neeg uas muaj kev lees paub txog keeb kwm ntawm DKD (tsis muaj kev tiv thaiv). Qee cov enzymes koom nrog hauv cov piam thaj metabolism thiab cov tshuaj tiv thaiv oxidation tau pom tias nce ntxiv hauv kev tiv thaiv glomeruli, thiab tshwj xeeb, pyruvate kinase M2 (PKM2) kev qhia thiab kev ua haujlwm tau raug kho. Hauv kev tshawb fawb siv tshuab siv cov kua nplaum-kho cov podocytes thiab STZ-txhaj nas, nws tau lees paub tias PKM2 kev ua haujlwm tau txo qis hauv DKD nas qauv, tias PKM downregulation tau pab txhawb rau DKD exacerbation thiab cov tshuaj siv tshuaj ntawm PKM2 thim rov qab qhov nce hauv cov piam thaj metabolites. thiab mitochondrial dysfunction. Ib yam li ntawd, qhov txo qis hauv pyruvate kinase activation ua rau cov nyhuv Warburg hauv kev mob qog noj ntshav [38].

Lwm yam tseem ceeb tshaj tawm los ua kom muaj kev cuam tshuam Warburg hauv DKD suav nrog sphingomyelin thiab fumarate tsub zuj zuj [39]. Matrix-pab laser desorption / ionization mass spectrometry imaging (MALDI-MSI) qhia qhov nce ntxiv ntawm ATP / AMP piv thiab ntawm ib hom sphingomyelin (SM(d18:1/16:0))) hauv glomeruli ntawm DKD nas. [40]. Hauv vitro, qhov sib ntxiv ntawm SM (d18: 1 / 16: 0) rau mesangial hlwb activated glycolysis. Fumarate tau raug txheeb xyuas tias yog ib qho tseem ceeb uas kho Nox4- raug mob hauv DKD [41]. Podocyte-specific induction ntawm Nox4 nyob rau hauv vivo recapitulated DKD-induced glomerular raug mob, thiab metabolomic tsom xam pom tau tias muaj zog fumarate, uas tau thim rov qab nrog Nox1 / Nox4 inhibition. Fumarate tuaj yeem ua haujlwm zoo li hypoxia-inducible factor (HIF) stabilizer, uas tuaj yeem ua rau lub zog ntawm glycolysis thiab kev tawm tsam ntawm OXPHOS.

3.2. Cov tshuaj toxicity ntawm cov piam thaj Metabolism

Plaub txoj hauv kev loj tshaj plaws los ntawm glycolysis paub tias tsim cov tshuaj lom neeg nruab nrab metabolites: txoj hauv kev polyol, txoj hauv kev hexosamine,advanced glycation kawg cov khoom(AGEs) txoj kev, thiab cov protein kinase C (PKC) txoj kev [12] (Daim duab 3). Inhibition ntawm txhua txoj hauv kev no ameliorateshyperglycemia ua rau raug mobnyob rau hauv preclinical qauv [42–45]. Qhov tseem ceeb, kev ua kom ib qho ntawm txoj hauv kev no tuaj yeem thim rov qab tam sim nrog kev kho ntawm euglycemia.

Hauv particular, qib ntawm 3-deoxyglucosone (3DG) thiab methylglyoxal (MGO), cov tswv cuab ntawm cov kab mob reactive carbonyl (RCS) uas yog tsim los ntawm degradation ntawm glyceraldehyde hauv AGE txoj hauv kev, yog nce nrog kev ua kom glycolysis. RCS muaj cov pab pawg carbonyl reactive heev thiab tuaj yeem hloov kho cov protein thiab DNA. Proteins glycated los ntawm RCS ua rau tsim AGEs. Extracellular AGEs tuaj yeem ua rau muaj kev sib txuas ntawm matrices, ua rau cov hlab ntsha khov [46]. AGEs tseem tuaj yeem khi rau receptors rau AGE (RAGE) thiab hloov ntau yam teeb liab mus rau hauv cov hlwb, suav nrog kev ua haujlwm ntawm nuclear-κB (NF-κB) ua rau ROS tsim, mob thiab fibrosis [47].

Daim duab 3. Glycolysis thiab branching pathways. Nyob rau hauv ib puag ncig-qabzib siab ntawm DKD, glycolysis yog nce thiab OXPHOS txo qis, ua rau muaj cov tshuaj lom metabolites tsim nyob rau hauv txoj hauv kev ntawm glycolysis. AGE, advanced glycation kawg khoom; DAG, diacylglycerol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; OXPHOS, oxidative phosphorylation; PKC, protein kinase C; PKM, pyruvate kinase M; TCA voj voog, tricarboxylic acid voj voog; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.

4. Non-Glucose-Induced Mitochondrial Dysfunction hauv DKD

Txawm hais tias hyperglycemia yog qhov tseem ceeb hauv kev txhim kho DKD, lwm yam cuam tshuam hauv DKD kuj tuaj yeem ua rau mitochondrial tsis ua haujlwm. Dyslipidemia thiab lipid overload yog ib qho teeb meem tshwm sim hauv DKD, thiab hypoxia hauv tubulointerstium tshwm sim tsis hais txog qhov ua rau mob raum mob (CKD) [48]. Endothelin-1 (Edn1) yog thawj zaug tau txheeb pom tias yog qhov qis qis ntawm kev hloov pauv kev loj hlob- (TGF- ) hauv tus qauv ntawm focal segmental glomerulosclerosis (FSGS) thiab pom tias ua rau albuminuria ntawm mtROS hauv glomerular endothelial hlwb. Tom qab ntawd, tib txoj kev taw qhia kuj tau pom tias yuav raug kho hauv DKD [49,50]. Hauv seem no, peb tham txog lub luag haujlwm ntawm cov xwm txheej no hauv kev txhim kho thiab kev loj hlob ntawm DKD hauv mitochondrial dysfunction.

4.1. Lipotoxicity

Nyob rau hauv lub raum biopsies ntawm cov neeg mob nrog DKD, ntau lipid droplet tsub zuj zuj tau pom los ntawm electron microscopy nyob rau hauv glomerular endothelial hlwb, podocytes, thiab tubular hlwb piv rau noj qab haus huv counterparts [51,52]. Kev tshuaj ntsuam caj ces ntawm cov qauv no tau qhia txog kev txo qis ntawm fatty acid oxidation (FAO) ntsig txog cov noob suav nrog peroxisome proliferator-activated receptor (PPAR), carnitine palmitoyltransferase 1 (CPT1), acyl-CoA oxidase, thiab L-FABP; upregulation ntawm cov roj cholesterol receptors nrog rau cov lipoprotein tsawg (LDL) receptors, oxidized LDL receptors, thiab acetylated LDL receptors; thiab kev txo qis ntawm cov roj cholesterol-efflux cov noob muaj xws li ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), thiab apolipoprotein (APOE) [51]. Thaum lub downregulation ntawm FAO-txog noob caj noob ces qhia ib tug txo nyob rau hauv mitochondrial lipid metabolism raws li qhov ua rau ntawm lipid tsub zuj zuj, lipid tsub zuj zuj nws tus kheej tuaj yeem ua rau mitochondrial tsis ua haujlwm. Peb yav dhau los tau pom tias tib neeg podocytes kho nrog cov ntshav ntawm cov neeg mob DKD qhia tau hais tias muaj cov qog necrosis (TNF) ntau ntxiv thiab hauv zos es tsis yog qhov systemic TNF ua rau cov roj cholesterol dawb thiab raug mob los ntawm kev tawm tsam ntawm ABCA1 hauv podocytes [53,54]. Qhov tseem ceeb, ABCA1 inhibition induced cardiolipin tsub zuj zuj thiab peroxidation nyob rau hauv mitochondria, sensitizing podocytes rau raug mob [55]. ABCA1 overexpression lossis inhibition ntawm cardiolipin peroxidation los ntawm elamipretide cawm podocyte raug mob hauv kev sim DKD.

Tubular hlwb xav tau ntau npaum li cas ntawm ATP rau solute reabsorption thiab nyob ntawm FAO vim fatty acids yield ntau ATP ib gram dua li lwm yam zog [56]. Nyob rau theem pib ntawm kev mob ntshav qab zib, FAO yog nce los ntawm kev nce FA flux, thiab ROS ntau lawm yog vim FAO, tshwj xeeb tshaj yog rau electron leakage ntawm electron hloov flavoprotein uas shuttles electrons los ntawm acyl-CoA dehydrogenases rau coenzyme Q [57]. Txawm li cas los xij, FAO thaum kawg tau txo qis hauv cov ntshav qab zib uas tau piav qhia ua ntej [51,58].

Tubular hlwb nyob rau hauv cov neeg mob nrog DKD yog feem ntau raug rau fatty acid-bound albumin txij li thaum dyslipidemia thiab proteinuria feem ntau nrog ntshav qab zib mellitus. Whereas albumin nws tus kheej tuaj yeem ua rau tubular cell puas ntawm nws cov reabsorption, FA-bound albumin tau pom tias ua rau muaj kev puas tsuaj rau tubular ntau dua [59,60]. Cytotoxicity tshwm sim los ntawm FA los yog glycated albumin tau pom tias yuav tsum tau kho los ntawm kev uptake ntawm cov protein pawg ntawm kev sib txawv 36 / FA translocase (CD36 / FAT) nyob rau hauv txhuam ciam teb rau tib neeg, nyob rau hauv sib piv rau ib txwm albu min reabsorption ntawm ib tug complex ntawm megalin, cubilin thiab amnionless [61]. Ntxiv nrog rau reabsorption, cov synthesis ntawm FA kuj yog upregulated [62,63]. FAs yog esterified los ntawm long-chain acyl-CoA (LC-CoA) synthetase (ACSL), uas yog upregulated nyob rau hauv ob qho tib si nas db / db qauv thiab tib neeg DKD raum kuaj [64,65]. LC-CoA raug xa mus rau mitochondria ntawm CPT1 thiab CPT2 los tsim ATP ntawm FAO thiab unmetabolized LC-CoA yog cleaved los yog khaws cia rau hauv lipid droplets los tiv thaiv lipotoxicity. Thaum lub peev xwm buffering tau saturated, LC-CoA ua haujlwm ua tus inhibitor ntawm Na + / H + exchanger 1 (NHE1) thiab phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P2] khi ua rau apoptosis nyob rau hauv proximal tubular. cev [66].

Kev txhim kho caj ces thiab tshuaj kho mob ntawm FAO tuaj yeem sawv cev rau kev kho mob tshiab rau cov neeg mob DKD. Transgenic qhia ntawm PCG1 thiab kev kho mob fenofibrate ameliorated tubular cell apoptosis los ntawm kev kho dua ntawm CPTs thiab / lossis acyl-CoA oxidases [58,67].

4.2. Hypoxia

Tubulointerstitial hypoxia paub tias yog txoj hauv kev kawg ntawm CKD kev loj hlob [48]. Txawm hais tias qhov ua rau tus kab mob no, hypoxia tuaj yeem tshwm sim vim qhov txo qis ntawm cov pa oxygen los ntawm cov ntshav ntws vim tias tsis muaj vasodilation, poob ntawm vasculature, fibrosis, anemia, nce oxygen xav tau vim muaj zog dua solute reabsorption, thiab inefficient ATP ntau lawm vim mitochondrial uncoupling, uas yog cov txheej txheem sib koom hauv CKD.

Tsis ntev los no, cov txheej txheem uas mob hypoxia ua rau mtROS ntau lawm hauv ETC tau tshwm sim [68]. Mob hypoxia ua rau muaj kev hloov pauv hauv Complex I, ua rau kev ua kom Na+/Ca2+ exchanger nyob rau hauv lub puab mitochondrial membrane. Na + ntshuam mus rau hauv matrix ces cuam tshuam nrog phospholipids kom txo cov membrane fluidity, ua rau tsis muaj peev xwm ntawm ubiquinone dawb txav ntawm Complex II thiab Complex III. Yog li, Complex III tsim ROS.

Hypoxia tau ntev lawm suav hais tias yog ib tug ncaj qha suppressor ntawm OXPHOS vim hais tias oxygen yog indispensable raws li ib tug receiver ntawm electrons nyob rau hauv ETC. Txawm li cas los xij, kom txo qis OXPHOS kom nrawm thiab ncaj qha, cov pa oxygen concentration yuav tsum tsawg li 0.3% [69]. Nyob rau hauv me me thiab ntev hypoxia, HIF1 ua raws li tus neeg nruab nrab los tswj OXPHOS thiab nce glycolysis txhawm rau tiv thaiv ROS ntau lawm. HIF1 hloov kho ETC complexes thiab txhawb cov metabolic hloov ntawm aerobic OXPHOS rau anaerobic glycolysis [69]. Txawm li cas los xij, hauv kev mob hypoxia, cov kev hloov pauv no txwv lub peev xwm mitochondrial los tsim ATP thiab tuaj yeem ua rau ATP tsis txaus, tej zaum ua rau cytotoxicity.

4.3. Endothelin-1 (Edn1)/Edn1 Receptor Hom A (Endra) Kev Qhia

Endothelin-1 (Edn1) yog thawj tus yam ntxwv raws li ib qho kev taw qhia molecule tso tawm los ntawm podocytes hauv TGF- -induced FSGS [49]. Kuj ceeb tias, Edn1 ua rau mtROS, txo qis lub peev xwm ua pa thiab ua rau mtDNA kev puas tsuaj hauv cov hlwb endothelial ntawm Edn1 receptor hom A (Ednra) ua kom, tab sis qhov no tsis pom hauv podocytes. Txoj kev no induces glycosaminoglycan degradation nyob rau hauv lub endothelial nto txheej, ua rau poob ntawm fenestration [70]. Interestingly, EDNRA kev ua kom nyob rau hauv endothelial hlwb kuj yuav tsum tau rau podocyte ko taw txheej txheem effacement thiab apoptosis [49].

Lub luag haujlwm zoo sib xws ntawm mtROS thiab EDNRA hauv cov hlwb endothelial thiab Edn1 kuj tau piav qhia hauv DKD [50]. Circulating Edn1 tau nce hauv cov neeg mob ntshav qab zib thiab nas [50,71]. Qhov tseem ceeb, Ednra tsis pom nyob rau hauv glomeruli ntawm tib neeg lub raum noj qab haus huv lossis DKD-resistant C57BL / 6J nas tab sis muaj nyob rau hauv cov tib neeg DKD ob lub raum thiab ntshav qab zib DBA / 2J nas. Ednra tuaj yeem raug ntxias hauv cov ntshav qabzib-kho podocytes, tab sis cov podocytes no tsis qhia Edn1, cuam tshuam rau lwm hom cell lossis stimuli hauv qhov teeb meem no [50]. Yog li, Edn1 / Ednra signaling yog qhov tseem ceeb hauv kev sib txuas lus sib txuas ntawm cov podocytes thiab endothelial hlwb ntawm mitochondrial dysfunction hauv FSGS thiab DKD.

Lwm txoj hauv kev vasoactive, renin-angiotensin-aldosterone system (RAAS), kuj paub tias koom nrog CKD kev loj hlob, suav nrog hauv DKD. Ib cag los ntawm kev cuam tshuam tsis zoo ntawm kev ua kom lub cev thiab cov ntshav siab, kev kho mob angiotensin II tau pom tias ua rau mtROS ntau lawm thiab mitochondrial fragmentation hauv podocytes ob leeg hauv vivo thiab hauv vitro, uas tuaj yeem thim rov qab los ntawm mitoquinone, mitochondria-targeted antioxidant [72].

5. Cov lus xaus

Mitochondrial dysfunction plays lub luag haujlwm tseem ceeb hauv kev txhim kho thiab kev loj hlob ntawm DKD. Yog li, tsom mus rau mitochondrial dysfunction hauv DKD tuaj yeem sawv cev rau cov tswv yim kho tshiab rau cov neeg mob DKD. Txawm li cas los xij, raws li tuaj yeem kawm tau los ntawm cov kev tshawb fawb tshawb xyuas cov txiaj ntsig zoo ntawm kev tswj hwm cov tshuaj tiv thaiv kab mob antioxidant raws li kev kho rau DKD, nws zoo li tias kev cuam tshuam hauv mitochondrial tsis ua haujlwm yuav tsum yog hom cell- thiab cov ntsiab lus tshwj xeeb. Lwm qhov kev xav tsis txaus ntseeg yog hnub nyoog- thiab kev sib deev sib txawv ntawm kev ua haujlwm mitochondrial hauv DKD. Txawm hais tias muaj hnub nyoog yog qhov tseem ceeb uas cuam tshuam rau kev ua haujlwm ntawm mitochondrial thiab kev loj hlob thiab kev loj hlob ntawm DKD, tsis muaj ntau yam paub txog cov txheej txheem tseeb. Hais txog kev sib deev, ntau qhov sib txawv ntawm cov txiv neej thiab poj niam hauv mitochondria ntawm qee cov ntaub so ntswg, thiab cov tshuaj estrogen thiab tejzaum nws yog testosterone tuaj yeem kho lub raum mitochondrial bioenergetics [73]. Kev tshawb nrhiav ntxiv yog xav tau los piav qhia cov txheej txheem tseeb uas ua rau mitochondrial dysfunction hauv DKD, raws li qhov kev tshawb pom tuaj yeem siv rau cov neeg mob thiab hloov lawv qhov kev kuaj mob.

Tus sau kev koom tes:Conceptualization, MI, MZG thiab AF; kev sau ntawv-kev npaj ua ntej, MI; sau-saib xyuas thiab kho, MI, SM, thiab AF Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Nyiaj txiag:MI tau txais kev txhawb nqa los ntawm Manpei Suzuki Diabetes Foundation. AF thiab SM tau txais kev txhawb nqa los ntawm National Institutes of Health pab nyiaj R01DK117599, R01DK104753 thiab R01CA227493. AF kuj tseem txhawb nqa los ntawm U54DK083912, UM1DK100846, U01DK116101 thiab UL1TR000460 (Miami Clinical Translational Science Institute).

Institutional Review Board Statement:Tsis siv tau

.INformed Consent Statement:Tsis siv tau.

Cov ntaub ntawv muaj nyob:Tsis siv tau.