Changes in mitochondrial complex I activity and coenzyme Q binding site in Leber's hereditary optic neuropathy (LHON)

1997 ◽  
Vol 18 ◽  
pp. 263-267 ◽  
Author(s):  
A. Ghelli ◽  
M. Degli Esposti ◽  
V. Carelli ◽  
G. Lenaz
Keyword(s):  
Binding Site ◽  
Optic Neuropathy ◽  
Complex I ◽  
Coenzyme Q ◽  
Mitochondrial Complex I ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Mitochondrial Complex ◽  
Complex I Activity ◽  
Hereditary Optic Neuropathy

scholarly journals Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy

2021 ◽  
Author(s):  
Sarah L. Stenton ◽  
Natalia L. Sheremet ◽  
Claudia B. Catarino ◽  
Natalia Andreeva ◽  
Zahra Assouline ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Complex I ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Hereditary Optic Neuropathy

scholarly journals Increased Protein S-Glutathionylation in Leber’s Hereditary Optic Neuropathy (LHON)

2020 ◽  
Vol 21 (8) ◽  
pp. 3027 ◽  
Author(s):  
Lei Zhou ◽  
James Chun Yip Chan ◽  
Stephanie Chupin ◽  
Naïg Gueguen ◽  
Valérie Desquiret-Dumas ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Complex I ◽  
Protein Quality ◽  
3D Structure ◽  
Protein S ◽  
Cell Protein ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Complex I Deficiency ◽  
Hereditary Optic Neuropathy

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.

The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy

2004 ◽  
Vol 56 (5) ◽  
pp. 631-641 ◽  
Author(s):  
Maria Lucia Valentino ◽  
Piero Barboni ◽  
Anna Ghelli ◽  
Laura Bucchi ◽  
Chiara Rengo ◽  
...  
Keyword(s):  
Optic Neuropathy ◽  
Complex I ◽  
Hot Spot ◽  
Leber’S Hereditary Optic Neuropathy ◽  
Leber's Hereditary Optic Neuropathy ◽  
Hereditary Optic Neuropathy

scholarly journals Coenzyme Q1 as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and Nqo1-null mouse lung

2012 ◽  
Vol 302 (9) ◽  
pp. L949-L958 ◽  
Author(s):  
Robert D. Bongard ◽  
Charles R. Myers ◽  
Brian J. Lindemer ◽  
Shelley Baumgardt ◽  
Frank J. Gonzalez ◽  
...  
Keyword(s):  
Complex I ◽  
Coenzyme Q ◽  
Dry Weight ◽  
Mouse Lung ◽  
Null Mouse ◽  
Mitochondrial Complex I ◽  
Wild Type ◽  
Mitochondrial Complex ◽  
Complex I Activity ◽  
The Impact

Previous studies showed that coenzyme Q1 (CoQ1) reduction on passage through the rat pulmonary circulation was catalyzed by NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex I, but that NQO1 genotype was not a factor in CoQ1 reduction on passage through the mouse lung. The aim of the present study was to evaluate the complex I contribution to CoQ1 reduction in the isolated perfused wild-type (NQO1+/+) and Nqo1-null (NQO1−/−) mouse lung. CoQ1 reduction was measured as the steady-state pulmonary venous CoQ1 hydroquinone (CoQ1H2) efflux rate during infusion of CoQ1 into the pulmonary arterial inflow. CoQ1H2 efflux rates during infusion of 50 μM CoQ1 were not significantly different for NQO1+/+ and NQO1−/− lungs (0.80 ± 0.03 and 0.68 ± 0.07 μmol·min−1·g lung dry wt−1, respectively, P > 0.05). The mitochondrial complex I inhibitor rotenone depressed CoQ1H2 efflux rates for both genotypes (0.19 ± 0.08 and 0.08 ± 0.04 μmol·min−1·g lung dry wt−1 for NQO1+/+ and NQO1−/−, respectively, P < 0.05). Exposure of mice to 100% O2 for 48 h also depressed CoQ1H2 efflux rates in NQO1+/+ and NQO1−/− lungs (0.43 ± 0.03 and 0.11 ± 0.04 μmol·min−1·g lung dry wt−1, respectively, P < 0.05 by ANOVA). The impact of rotenone or hyperoxia on CoQ1 redox metabolism could not be attributed to effects on lung wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total venous effluent CoQ1 recoveries, the latter measured by spectrophotometry or mass spectrometry. Complex I activity in mitochondria-enriched lung fractions was depressed in hyperoxia-exposed lungs for both genotypes. This study provides new evidence for the potential utility of CoQ1 as a nondestructive indicator of the impact of pharmacological or pathological exposures on complex I activity in the intact perfused mouse lung.

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