Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.
View / Open Files
Authors
Ayer, Anita
Suarna, Cacang
Maghzal, Ghassan J
Sheipouri, Diba
Lee, Kevin J
Bradley, Michelle C
Fernández-Del-Rio, Lucía
Kong, Stephanie My
van der Veen, Jelske N
Yang, Andrian
Ho, Joshua W K
Clarke, Steven G
James, David E
Dawes, Ian W
Vance, Dennis E
Clarke, Catherine F
Jacobs, René L
Stocker, Roland
Publication Date
2021-09-08Journal Title
Redox biology
ISSN
2213-2317
Volume
46
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ayer, A., Fazakerley, D. J., Suarna, C., Maghzal, G. J., Sheipouri, D., Lee, K. J., Bradley, M. C., et al. (2021). Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.. Redox biology, 46 https://doi.org/10.1016/j.redox.2021.102127
Abstract
Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.
Keywords
Mitochondria, Reactive oxygen species, Coenzyme Q, Insulin resistance, S-Adenosylmethionine, S-adenosylhomocysteine, Pemt
Sponsorship
Canadian Institutes of Health Research (DP150102408, MOP 5182, MCB-1714569, 1111632, MOP 33505)
National Science Foundation (MOP 5182, DP150102408, MOP 33505, 1111632, MCB-1714569)
National Health and Medical Research Council (DP150102408, MOP 33505, 1111632, MCB-1714569, MOP 5182)
Australian Research Council (DP150102408, MOP 33505, MCB-1714569, 1111632, MOP 5182)
Identifiers
PMC8435697, 34521065
External DOI: https://doi.org/10.1016/j.redox.2021.102127
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329532
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.