Proteomic Profiling Reveals Increased Glycolysis, Decreased Oxidoreductase Activity and Fatty Acid Degradation in Skin Derived Fibroblasts from LHON Patients Bearing M.G11778A

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Nov 11

PMID 36358916

Authors

Shun Yao

Xiaoli Zhang

Xiuxiu Jin

Mingzhu Yang

Ya Li

Lin Yang

Jin Xu

Bo Lei

Affiliations

Soon will be listed here.

Abstract

LHON is a common blinding inherited optic neuropathy caused by mutations in mitochondrial genes. In this study, by using skin fibroblasts derived from LHON patients with the most common m.G11778A mutation and healthy objects, we performed proteomic analysis to document changes in molecular proteins, signaling pathways and cellular activities. Furthermore, the results were confirmed by functional studies. A total of 860 differential expression proteins were identified, containing 624 upregulated and 236 downregulated proteins. Bioinformatics analysis revealed increased glycolysis in LHON fibroblasts. A glycolysis stress test showed that ECAR (extra-cellular acidification rate) values increased, indicating an enhanced level of glycolysis in LHON fibroblasts. Downregulated proteins were mainly enriched in oxidoreductase activity. Cellular experiments verified high levels of ROS in LHON fibroblasts, indicating the presence of oxidative damage. KEGG analysis also showed the metabolic disturbance of fatty acid in LHON cells. This study provided a proteomic profile of skin fibroblasts derived from LHON patients bearing m.G11778A. Increased levels of glycolysis, decreased oxidoreductase activity and fatty acid metabolism could represent the in-depth mechanisms of mitochondrial dysfunction mediated by the mutation. The results provided further evidence that LHON fibroblast could be an alternative model for investigating the devastating disease.

Citing Articles

Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber's hereditary optic neuropathy (LHON).

Nair A, Selvakumar A, Gopalarethinam J, Abishek Kumar B, Vellingiri B, Subramaniam M Hum Genome Var. 2024; 11(1):6.

PMID: 38272864 PMC: 10810857. DOI: 10.1038/s41439-023-00258-5.

References

del Hoyo P, Garcia-Redondo A, de Bustos F, Molina J, Sayed Y, Alonso-Navarro H . Oxidative stress in skin fibroblasts cultures of patients with Huntington's disease. Neurochem Res. 2006; 31(9):1103-9. DOI: 10.1007/s11064-006-9110-2. View

Ho J, Barbi de Moura M, Lin Y, Vincent G, Thorne S, Duncan L . Importance of glycolysis and oxidative phosphorylation in advanced melanoma. Mol Cancer. 2012; 11:76. PMC: 3537610. DOI: 10.1186/1476-4598-11-76. View

Wang X, An P, Gu Z, Luo Y, Luo J . Mitochondrial Metal Ion Transport in Cell Metabolism and Disease. Int J Mol Sci. 2021; 22(14). PMC: 8305404. DOI: 10.3390/ijms22147525. View

Rizzardini M, Mangolini A, Lupi M, Ubezio P, Bendotti C, Cantoni L . Low levels of ALS-linked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuron-like cells. J Neurol Sci. 2005; 232(1-2):95-103. DOI: 10.1016/j.jns.2005.02.004. View

Onesto E, Colombrita C, Gumina V, Borghi M, Dusi S, Doretti A . Gene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts. Acta Neuropathol Commun. 2016; 4(1):47. PMC: 4858818. DOI: 10.1186/s40478-016-0316-5. View

Xie S, Zhang J, Sun J, Zhang M, Zhao F, Wei Q . Mitochondrial haplogroup D4j specific variant m.11696G > a(MT-ND4) may increase the penetrance and expressivity of the LHON-associated m.11778G > a mutation in Chinese pedigrees. Mitochondrial DNA A DNA Mapp Seq Anal. 2016; 28(3):434-441. DOI: 10.3109/19401736.2015.1136304. View

Galloway C, Yoon Y . Mitochondrial morphology in metabolic diseases. Antioxid Redox Signal. 2012; 19(4):415-30. PMC: 3700066. DOI: 10.1089/ars.2012.4779. View

Jiao L, Du X, Li Y, Jiao Q, Jiang H . Role of Mitophagy in neurodegenerative Diseases and potential tagarts for Therapy. Mol Biol Rep. 2022; 49(11):10749-10760. DOI: 10.1007/s11033-022-07738-x. View

Schonfeld P, Wojtczak L . Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med. 2008; 45(3):231-41. DOI: 10.1016/j.freeradbiomed.2008.04.029. View

10.

Hage R, Vignal-Clermont C . Leber Hereditary Optic Neuropathy: Review of Treatment and Management. Front Neurol. 2021; 12:651639. PMC: 8187781. DOI: 10.3389/fneur.2021.651639. View

11.

Yu-Wai-Man P, Griffiths P, Howell N, Turnbull D, Chinnery P . The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England. Am J Hum Genet. 2016; 98(6):1271. PMC: 5690579. DOI: 10.1016/j.ajhg.2016.05.015. View

12.

JOHNS D, Neufeld M, Park R . An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun. 1992; 187(3):1551-7. DOI: 10.1016/0006-291x(92)90479-5. View

13.

Geldon S, Fernandez-Vizarra E, Tokatlidis K . Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells. Front Cell Dev Biol. 2021; 9:720656. PMC: 8452992. DOI: 10.3389/fcell.2021.720656. View

14.

Bertholet A, Delerue T, Millet A, Moulis M, David C, Daloyau M . Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis. 2015; 90:3-19. DOI: 10.1016/j.nbd.2015.10.011. View

15.

Yao S, Zhou Q, Yang M, Li Y, Jin X, Guo Q . Multi-mtDNA Variants May Be a Factor Contributing to Mitochondrial Function Variety in the Skin-Derived Fibroblasts of Leber's Hereditary Optic Neuropathy Patients. Front Mol Neurosci. 2022; 15:920221. PMC: 9326446. DOI: 10.3389/fnmol.2022.920221. View

16.

Ma J, Chen T, Wu S, Yang C, Bai M, Shu K . iProX: an integrated proteome resource. Nucleic Acids Res. 2018; 47(D1):D1211-D1217. PMC: 6323926. DOI: 10.1093/nar/gky869. View

17.

Fernandez-Moncada I, Ruminot I, Robles-Maldonado D, Alegria K, Deitmer J, Barros L . Neuronal control of astrocytic respiration through a variant of the Crabtree effect. Proc Natl Acad Sci U S A. 2018; 115(7):1623-1628. PMC: 5816174. DOI: 10.1073/pnas.1716469115. View

18.

Magini A, Urbanelli L, Ciccarone V, Tancini B, Polidoro M, Timperio A . Fibroblasts from PS1 mutated pre-symptomatic subjects and Alzheimer's disease patients share a unique protein levels profile. J Alzheimers Dis. 2010; 21(2):431-44. DOI: 10.3233/JAD-2010-091522. View

19.

Lin C, Sharpley M, Fan W, Waymire K, Sadun A, Carelli V . Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2012; 109(49):20065-70. PMC: 3523873. DOI: 10.1073/pnas.1217113109. View

20.

Jin X, Zhang X, Liu J, Wang W, Liu M, Yang L . Retinal Proteomic Alterations and Combined Transcriptomic-Proteomic Analysis in the Early Stages of Progression of a Mouse Model of X-Linked Retinoschisis. Cells. 2022; 11(14). PMC: 9321393. DOI: 10.3390/cells11142150. View