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Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death

Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the pr...

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Autores principales: Balsa, Eduardo, Perry, Elizabeth A., Bennett, Christopher F., Jedrychowski, Mark, Gygi, Steven P., Doench, John G., Puigserver, Pere
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264245/
https://www.ncbi.nlm.nih.gov/pubmed/32483148
http://dx.doi.org/10.1038/s41467-020-16423-1
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author Balsa, Eduardo
Perry, Elizabeth A.
Bennett, Christopher F.
Jedrychowski, Mark
Gygi, Steven P.
Doench, John G.
Puigserver, Pere
author_facet Balsa, Eduardo
Perry, Elizabeth A.
Bennett, Christopher F.
Jedrychowski, Mark
Gygi, Steven P.
Doench, John G.
Puigserver, Pere
author_sort Balsa, Eduardo
collection PubMed
description Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong increases in inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.
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spelling pubmed-72642452020-06-12 Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death Balsa, Eduardo Perry, Elizabeth A. Bennett, Christopher F. Jedrychowski, Mark Gygi, Steven P. Doench, John G. Puigserver, Pere Nat Commun Article Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong increases in inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death. Nature Publishing Group UK 2020-06-01 /pmc/articles/PMC7264245/ /pubmed/32483148 http://dx.doi.org/10.1038/s41467-020-16423-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Balsa, Eduardo
Perry, Elizabeth A.
Bennett, Christopher F.
Jedrychowski, Mark
Gygi, Steven P.
Doench, John G.
Puigserver, Pere
Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
title Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
title_full Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
title_fullStr Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
title_full_unstemmed Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
title_short Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
title_sort defective nadph production in mitochondrial disease complex i causes inflammation and cell death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264245/
https://www.ncbi.nlm.nih.gov/pubmed/32483148
http://dx.doi.org/10.1038/s41467-020-16423-1
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