A Combined Model of Human iPSC-Derived Liver Organoids and Hepatocytes Reveals Ferroptosis in DGUOK Mutant mtDNA Depletion Syndrome.
A Combined Model of Human iPSC-Derived Liver Organoids and Hepatocytes Reveals Ferroptosis in DGUOK Mutant mtDNA Depletion Syndrome.
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人类 iPSC 来源的肝脏类器官和肝细胞的联合模型揭示了 DGUOK 突变 mtDNA 耗竭综合征中的铁死亡
DOI：
10.1002/advs.202004680
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Guo J;Duan L;He X;Li S;Wu Y;Xiang G;Bao F;Yang L;Shi H;Gao M;Zheng L;Hu H;Liu X
线粒体DNA缺失综合征（mitochondrialDNAdepletionsyndrome，MDS）是一组由脱氧核糖核苷激酶（deoxyribonucleosidedkinase，DGUOK）等基因突变引起的严重遗传性疾病。绝大多数DGUOK突变型MDS患者发生铁过载，进展为严重肝衰竭。然而，铁超载和肝损伤的病理机制仍然没有被发现。在这里，两名患者的皮肤成纤维细胞被重编程为诱导多能干细胞（iPSC），然后通过CRISPR/Cas9进行校正。产生患者特异性iPSC和校正的iPSC衍生的高纯度肝细胞类器官（iHep-Orgs）和肝细胞样细胞（iHep）作为用于研究肝脏病理学的细胞模型。DGUOK突变体iHep和iHep-Orgs，而不是对照和校正的iHep-Orgs，对铁过载诱导的铁凋亡更敏感，这可以通过N-乙酰半胱氨酸（NAC）来挽救。从机械上讲，这种铁凋亡是由核受体共激活因子4（NCOA 4）依赖性溶酶体中铁蛋白降解和细胞不稳定铁释放介导的过程。该研究揭示了该综合征的潜在病理机制和可行的治疗策略，是遗传性肝病中的第一个纯iHep‐Orgs模型。
Mitochondrial DNA depletion syndrome (MDS) is a group of severe inherited disorders caused by mutations in genes, such as deoxyribonucleoside kinase (DGUOK). A great majority of DGUOK mutant MDS patients develop iron overload progressing to severe liver failure. However, the pathological mechanisms connecting iron overload and hepatic damage remains uncovered. Here, two patients’ skin fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs) and then corrected by CRISPR/Cas9. Patient‐specific iPSCs and corrected iPSCs‐derived high purity hepatocyte organoids (iHep‐Orgs) and hepatocyte‐like cells (iHep) are generated as cellular models for studying hepatic pathology. DGUOK mutant iHep and iHep‐Orgs, but not control and corrected one, are more sensitive to iron overload‐induced ferroptosis, which can be rescued by N‐Acetylcysteine (NAC). Mechanically, this ferroptosis is a process mediated by nuclear receptor co‐activator 4 (NCOA4)‐dependent degradation of ferritin in lysosome and cellular labile iron release. This study reveals the underlying pathological mechanisms and the viable therapeutic strategies of this syndrome, and is the first pure iHep‐Orgs model in hereditary liver diseases.
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影响因子：
64.8
作者：
Mancias, Joseph D.;Wang, Xiaoxu;Gygi, Steven P.;Harper, J. Wade;Kimmelman, Alec C.
通讯作者：
Kimmelman, Alec C.
影响因子：
5.6
作者：
de Andrade KQ;Moura FA;dos Santos JM;de Araújo OR;de Farias Santos JC;Goulart MO
通讯作者：
Goulart MO
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
14.8
作者：
Dekkers, Johanna F.;Alieva, Maria;Rios, Anne C.
通讯作者：
Rios, Anne C.
影响因子：
2.4
作者：
Pronicka, Ewa;Weglewska-Jurkiewicz, Anna;Taybert, Joanna;Pronicki, Maciej;Szymanska-Debinska, Tamara;Karkucinska-Wieckowska, Agnieszka;Jakobkiewicz-Banecka, Joanna;Kowalski, Pawel;Piekutowska-Abramczuk, Dorota;Pajdowska, Magdalena;Socha, Piotr;Sykut-Cegielska, Jolanta;Wegrzyn, Grzegorz
通讯作者：
Wegrzyn, Grzegorz