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Title: Increased protein S-glutathionylation in Leber’s hereditary optic neuropathy (LHON)
Authors: Zhou, Lei
Chan, James Chun Yip
Chupin, Stephanie
Gueguen, Naïg
Desquiret-Dumas, Valérie
Koh, Siew Kwan
Li, Jianguo
Gao, Yan
Deng, Lu
Verma, Chandra Shekhar
Beuerman, Roger W.
Chan, Eric Chun Yong
Milea, Dan
Reynier, Pascal
Keywords: Science::Biological sciences
Issue Date: 2020
Source: Zhou, L., Chan, J. C. Y., Chupin, S., Gueguen, N., Desquiret-Dumas, V., Koh, S. K., . . . Reynier, P. (2020). Increased protein S-glutathionylation in Leber’s hereditary optic neuropathy (LHON). International Journal of Molecular Sciences, 21(8), 3027-. doi:10.3390/ijms21083027
Journal: International Journal of Molecular Sciences
Abstract: Leber’s hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still unclear. Hypothesizing that oxidative stress related to Complex I deficiency may increase protein S-glutathionylation, we investigated the proteome-wide S-glutathionylation profiles in LHON (n = 11) and control (n = 7) fibroblasts, using the GluICAT platform that we recently developed. Glutathionylation was also studied in healthy fibroblasts (n = 6) after experimental Complex I inhibition. The significantly increased reactive oxygen species (ROS) production in the LHON group by Complex I was shown experimentally. Among the 540 proteins which were globally identified as glutathionylated, 79 showed a significantly increased glutathionylation (p < 0.05) in LHON and 94 in Complex I-inhibited fibroblasts. Approximately 42% (33/79) of the altered proteins were shared by the two groups, suggesting that Complex I deficiency was the main cause of increased glutathionylation. Among the 79 affected proteins in LHON fibroblasts, 23% (18/79) were involved in energetic metabolism, 31% (24/79) exhibited catalytic activity, 73% (58/79) showed various non-mitochondrial localizations, and 38% (30/79) affected the cell protein quality control. Integrated proteo-metabolomic analysis using our previous metabolomic study of LHON fibroblasts also revealed similar alterations of protein metabolism and, in particular, of aminoacyl-tRNA synthetases. S-glutathionylation is mainly known to be responsible for protein loss of function, and molecular dynamics simulations and 3D structure predictions confirmed such deleterious impacts on adenine nucleotide translocator 2 (ANT2), by weakening its affinity to ATP/ADP. Our study reveals a broad impact throughout the cell of Complex I-related LHON pathogenesis, involving a generalized protein stress response, and provides a therapeutic rationale for targeting S-glutathionylation by antioxidative strategies.
ISSN: 1661-6596
DOI: 10.3390/ijms21083027
Schools: School of Biological Sciences 
Rights: © 2020 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
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