@article{56e8a4a4f9544568a4a59641dafeabfb,
title = "Mitochondrial transport mediates survival of retinal ganglion cells in affected LHON patients",
abstract = "The mutations in the genes encoding the subunits of complex I of the mitochondrial electron transport chain are the most common cause of Leber's hereditary optic neuropathy (LHON), a maternal hereditary disease characterized by retinal ganglion cell (RGC) degeneration. The characteristics of incomplete penetrance indicate that nuclear genetic and environmental factors also determine phenotypic expression of LHON. Therefore, further understanding of the role of mutant mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit proteins and nuclear genetic factors/environmental effects in the etiology of LHON is needed. In this study, we generated human-induced pluripotent stem cells (hiPSCs) from healthy control, unaffected LHON mutation carrier, and affected LHON patient. hiPSC-derived RGCs were used to study the differences between affected and unaffected carriers of mitochondrial DNA point mutation m.11778G > A in the MT-ND4 gene. We found that both mutated cell lines were characterized by increase in reactive oxygen species production, however, only affected cell line had increased levels of apoptotic cells. We found a significant increase in retrograde mitochondria and a decrease in stationary mitochondria in the affected RGC axons. In addition, the messenger RNA and protein levels of KIF5A in the LHON-affected RGCs were significantly reduced. Antioxidant N-acetyl-L-cysteine could restore the expression of KIF5A and the normal pattern of mitochondrial movement in the affected RGCs. To conclude, we found essential differences in the mutually dependent processes of oxidative stress, mitochondrial transport and apoptosis between two LHON-specific mutation carrier RGC cell lines, asymptomatic carrier and disease-affected, and identified KIF5A as a central modulator of these differences.",
author = "Yang, {Tien Chun} and Yarmishyn, {Aliaksandr A.} and Yang, {Yi Ping} and Lu, {Pin Chen} and Chou, {Shih Jie} and Wang, {Mong Lien} and Lin, {Tai Chi} and Hwang, {De Kuang} and Chou, {Yu Bai} and Chen, {Shih Jen} and Yu, {Wei Kuang} and Wang, {An Guor} and Hsu, {Chih Chien} and Chiou, {Shih Hwa}",
note = "Funding Information: This study was funded by The Ministry of Science and Technology (MOST 106-2633-B-009-001, MOST106-2119-M-010-001, MOST106-2319-B-001-003, MOST106-3114-B-010-002, MOST 107-2119-M-010-001, MOST 107-2633-B-009-003, MOST107-2321-B-010-007, MOST107-2320-B-010-023, and MOST 107-2319-B-001-003); Academia Sinica and Ministry of Science and Technology (106-0210-01-15-02 and 107-0210-01-19-01); Academia Sinica (VTA107-V1-5-1 and VTA108-V1-5-3); the Ministry of Health and Welfare (MOHW)(106-TDU-B-211-113001, 107-TDU-B-211-123001 and 108-TDU-B-211-133001); National Health Research Institutes (NHRI) (EX106-AQ8 10621BI, EX107-10621BI and EX108-10621BI);Taipei Veterans General Hospital (V106C-001, V107C-139, V107E-002-2, 108E-002-2, and V108D46-004-MY2-1); Taipei Veterans General Hospital (TVGH) and National Taiwan University Hospital (NTU) Joint Project (VN106-02, VN107-16 and VN108-15); Veterans General Hospital (VGH), Tri-Service General Hospital (TSGH), National Defense Medical Center (NDMC), Academia Sinica (AS) Joint Research Program (VTA107/108-V1-5-1); Excellent Clinical Trail Center (MOHW106-TDU-B-211-113001, MOHW 107-TDU-B-211-123001, MOHW108-TDU-B-211-133001); the Ministry of Education (particularly supported through the SPROUT Project: the “Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B)” of National Chiao Tung University in Taiwan); the “Cancer Progression Research Center; and National Yang-Ming University (from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE)” in Taiwan). Publisher Copyright: {\textcopyright} 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2020",
month = jun,
day = "3",
doi = "10.1093/hmg/ddaa063",
language = "English",
volume = "29",
pages = "1454--1464",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "9",
}