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Article: PSCs Reveal PUFA-Provoked Mitochondrial Stress as a Central Node Potentiating RPE Degeneration in Bietti’s Crystalline Dystrophy

TitlePSCs Reveal PUFA-Provoked Mitochondrial Stress as a Central Node Potentiating RPE Degeneration in Bietti’s Crystalline Dystrophy
Authors
KeywordsBCD-iPSC disease model
CYP4V2 gene mutant PSC control
RPE
poly-unsaturated fatty acid
lipotoxicity
Issue Date2020
PublisherCell Press. The Journal's web site is located at https://www.cell.com/molecular-therapy-family/home
Citation
Molecular Therapy, 2020, v. 28 n. 12, p. 2642-2661 How to Cite?
AbstractBietti’s crystalline dystrophy (BCD) is an incurable retinal disorder caused by the polypeptide 2 of cytochrome P450 family 4 subfamily V (CYP4V2) mutations. Patients with BCD present degeneration of retinal pigmented epithelial (RPE) cells and consequent blindness. The lack of appropriate disease models and patients’ RPE cells limits our understanding of the pathological mechanism of RPE degeneration. In this study, using CYP4V2 mutant pluripotent stem cells as disease models, we demonstrated that RPE cells with CYP4V2 mutations presented a disrupted fatty acid homeostasis, which were characterized with excessive accumulation of poly-unsaturated fatty acid (PUFA), including arachidonic acid (AA) and eicosapentaenoic acid (EPA). The PUFA overload increased mitochondrial reactive oxygen species, impaired mitochondrial respiratory functions, and triggered mitochondrial stress-activated p53-independent apoptosis in CYP4V2 mutant RPE cells. Restoration of the mutant CYP4V2 using adeno-associated virus 2 (AAV2) can effectively reduce PUFA deposition, alleviate mitochondria oxidative stresses, and rescue RPE cell death in BCD RPE cells. Taken together, our results highlight a role of PUFA-induced mitochondrial damage as a central node to potentiate RPE degeneration in BCD patients. AAV2-mediated gene therapy may represent a feasible strategy for the treatment of BCD.
Persistent Identifierhttp://hdl.handle.net/10722/293224
ISSN
2019 Impact Factor: 8.986
2015 SCImago Journal Rankings: 3.374
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, Z-
dc.contributor.authorYan, B-
dc.contributor.authorGao, F-
dc.contributor.authorLi, Q-
dc.contributor.authorMeng, X-
dc.contributor.authorChen, P-
dc.contributor.authorZhou, L-
dc.contributor.authorDeng, W-
dc.contributor.authorLi, C-
dc.contributor.authorXu, W-
dc.contributor.authorHan, S-
dc.contributor.authorFeng, H-
dc.contributor.authorLi, Y-
dc.contributor.authorChen, J-
dc.contributor.authorYin, Z-
dc.contributor.authorLiao, C-
dc.contributor.authorTse, HF-
dc.contributor.authorXu, A-
dc.contributor.authorLian, Q-
dc.date.accessioned2020-11-23T08:13:38Z-
dc.date.available2020-11-23T08:13:38Z-
dc.date.issued2020-
dc.identifier.citationMolecular Therapy, 2020, v. 28 n. 12, p. 2642-2661-
dc.identifier.issn1525-0016-
dc.identifier.urihttp://hdl.handle.net/10722/293224-
dc.description.abstractBietti’s crystalline dystrophy (BCD) is an incurable retinal disorder caused by the polypeptide 2 of cytochrome P450 family 4 subfamily V (CYP4V2) mutations. Patients with BCD present degeneration of retinal pigmented epithelial (RPE) cells and consequent blindness. The lack of appropriate disease models and patients’ RPE cells limits our understanding of the pathological mechanism of RPE degeneration. In this study, using CYP4V2 mutant pluripotent stem cells as disease models, we demonstrated that RPE cells with CYP4V2 mutations presented a disrupted fatty acid homeostasis, which were characterized with excessive accumulation of poly-unsaturated fatty acid (PUFA), including arachidonic acid (AA) and eicosapentaenoic acid (EPA). The PUFA overload increased mitochondrial reactive oxygen species, impaired mitochondrial respiratory functions, and triggered mitochondrial stress-activated p53-independent apoptosis in CYP4V2 mutant RPE cells. Restoration of the mutant CYP4V2 using adeno-associated virus 2 (AAV2) can effectively reduce PUFA deposition, alleviate mitochondria oxidative stresses, and rescue RPE cell death in BCD RPE cells. Taken together, our results highlight a role of PUFA-induced mitochondrial damage as a central node to potentiate RPE degeneration in BCD patients. AAV2-mediated gene therapy may represent a feasible strategy for the treatment of BCD.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at https://www.cell.com/molecular-therapy-family/home-
dc.relation.ispartofMolecular Therapy-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectBCD-iPSC disease model-
dc.subjectCYP4V2 gene mutant PSC control-
dc.subjectRPE-
dc.subjectpoly-unsaturated fatty acid-
dc.subjectlipotoxicity-
dc.titlePSCs Reveal PUFA-Provoked Mitochondrial Stress as a Central Node Potentiating RPE Degeneration in Bietti’s Crystalline Dystrophy-
dc.typeArticle-
dc.identifier.emailZhang, Z: zhucex1a@hku.hk-
dc.identifier.emailYan, B: yanbin14@hku.hk-
dc.identifier.emailChen, P: pkchen@hku.hk-
dc.identifier.emailZhou, L: lenazhou@connect.hku.hk-
dc.identifier.emailDeng, W: wdeng@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.emailLian, Q: qzlian@hkucc.hku.hk-
dc.identifier.authorityYan, B=rp01940-
dc.identifier.authorityDeng, W=rp01640-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.authorityXu, A=rp00485-
dc.identifier.authorityLian, Q=rp00267-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ymthe.2020.07.024-
dc.identifier.pmid32755565-
dc.identifier.pmcidPMC7704739-
dc.identifier.hkuros319803-
dc.identifier.volume28-
dc.identifier.issue12-
dc.identifier.spage2642-
dc.identifier.epage2661-
dc.identifier.isiWOS:000596644000013-
dc.publisher.placeUnited States-

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