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