Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation

Chih-Yao Chung, Kritarth Singh, Vassilios N. Kotiadis, Gabriel E. Valdebenito, Jee Hwan Ahn, Emilie Topley, Joycelyn Tan, William D. Andrews, Benoit Bilanges, Robert D. S. Pitceathly, Gyorgy Szabadkai, Mariia Yuneva and Michael R. Duchen ()
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Chih-Yao Chung: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Kritarth Singh: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Vassilios N. Kotiadis: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Gabriel E. Valdebenito: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Jee Hwan Ahn: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Emilie Topley: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Joycelyn Tan: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
William D. Andrews: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Benoit Bilanges: UCL Cancer Institute
Robert D. S. Pitceathly: UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square
Gyorgy Szabadkai: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL
Mariia Yuneva: The Francis Crick Institute
Michael R. Duchen: Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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
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DOI: 10.1038/s41467-021-26746-2

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