TY - JOUR
T1 - Increased protein S-Glutathionylation in Leber’s hereditary optic neuropathy (LHON)
AU - Zhou, Lei
AU - Chan, James Chun Yip
AU - Chupin, Stephanie
AU - Gueguen, Naig
AU - Desquiret-Dumas, Valérie
AU - Koh, Siew Kwan
AU - Li, Jianguo
AU - Gao, Yan
AU - Deng, Lu
AU - Verma, Chandra
AU - Beuerman, Roger W.
AU - Chan, Eric Chun Yong
AU - Milea, Dan
AU - Reynier, And Pascal
N1 - Funding Information:
The authors are grateful for the grants provided by the Singapore National Medical Research Council (NMRC) Centre, Grants CG 2013 and CG 2017 awarded to the Singapore Eye Research Institute, and the SingHealth Foundation for the proteomics core facility at the Singapore Eye Research Institute. The author also thank A STAR/BMRC and NSCC for support.
Funding Information:
Funding: The authors are grateful for the grants provided by the Singapore National Medical Research Council (NMRC) Centre, Grants CG 2013 and CG 2017 awarded to the Singapore Eye Research Institute, and the SingHealth Foundation for the proteomics core facility at the Singapore Eye Research Institute. The author also thank A STAR/BMRC and NSCC for support.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/4/2
Y1 - 2020/4/2
N2 - 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.
AB - 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.
KW - Leber’s Hereditary Optic Neuropathy
KW - LHON
KW - Mitochondrial Complex I
KW - Proteomics
KW - S-glutathionylation
UR - http://www.scopus.com/inward/record.url?scp=85083982558&partnerID=8YFLogxK
U2 - 10.3390/ijms21083027
DO - 10.3390/ijms21083027
M3 - Journal article
C2 - 32344771
AN - SCOPUS:85083982558
SN - 1661-6596
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 8
M1 - 3027
ER -