eprintid: 10138061 rev_number: 19 eprint_status: archive userid: 608 dir: disk0/10/13/80/61 datestamp: 2021-11-11 12:04:03 lastmod: 2022-08-17 14:44:15 status_changed: 2021-11-11 12:04:03 type: article metadata_visibility: show creators_name: Chung, C-Y creators_name: Singh, K creators_name: Kotiadis, VN creators_name: Valdebenito, GE creators_name: Ahn, JH creators_name: Topley, E creators_name: Tan, J creators_name: Andrews, WD creators_name: Bilanges, B creators_name: Pitceathly, RDS creators_name: Szabadkai, G creators_name: Yuneva, M creators_name: Duchen, MR title: Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation ispublished: pub subjects: UCH divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F85 divisions: C08 divisions: D09 divisions: F96 divisions: C10 divisions: D19 divisions: G99 keywords: Energy metabolism, Metabolomics, Mitochondria, Nutrient signalling note: 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/. abstract: Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy – tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation. date: 2021-11-04 date_type: published publisher: Springer Science and Business Media LLC official_url: https://doi.org/10.1038/s41467-021-26746-2 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1898455 doi: 10.1038/s41467-021-26746-2 lyricists_name: Andrews, William lyricists_name: Bilanges, Benoit lyricists_name: Duchen, Michael lyricists_name: Pitceathly, Robert lyricists_name: Singh, Kritarth lyricists_name: Szabadkai, Gyorgy lyricists_name: Valdebenito Valdebenito, Gabriel lyricists_id: WDAND87 lyricists_id: BBILA89 lyricists_id: MRDUC42 lyricists_id: RDSPI25 lyricists_id: KSING94 lyricists_id: GSZAB15 lyricists_id: GEVAL87 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Nature Communications volume: 12 number: 1 article_number: 6409 citation: Chung, C-Y; Singh, K; Kotiadis, VN; Valdebenito, GE; Ahn, JH; Topley, E; Tan, J; ... Duchen, MR; + view all <#> Chung, C-Y; Singh, K; Kotiadis, VN; Valdebenito, GE; Ahn, JH; Topley, E; Tan, J; Andrews, WD; Bilanges, B; Pitceathly, RDS; Szabadkai, G; Yuneva, M; Duchen, MR; - view fewer <#> (2021) Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation. Nature Communications , 12 (1) , Article 6409. 10.1038/s41467-021-26746-2 <https://doi.org/10.1038/s41467-021-26746-2>. Green open access document_url: https://discovery-pp.ucl.ac.uk/id/eprint/10138061/1/s41467-021-26746-2.pdf