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

Author

Listed:
  • 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
    University of Padua
    The Francis Crick Institute)

  • Mariia Yuneva

    (The Francis Crick Institute)

  • Michael R. Duchen

    (Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL)

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.

Suggested Citation

  • 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, 2021. "Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26746-2
    DOI: 10.1038/s41467-021-26746-2
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    References listed on IDEAS

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    1. Yi-Fan Lin & Anna M. Schulz & Mark W. Pellegrino & Yun Lu & Shai Shaham & Cole M. Haynes, 2016. "Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response," Nature, Nature, vol. 533(7603), pages 416-419, May.
    2. Nikolay P. Kandul & Ting Zhang & Bruce A. Hay & Ming Guo, 2016. "Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila," Nature Communications, Nature, vol. 7(1), pages 1-11, December.
    3. Hugo Varet & Loraine Brillet-Guéguen & Jean-Yves Coppée & Marie-Agnès Dillies, 2016. "SARTools: A DESeq2- and EdgeR-Based R Pipeline for Comprehensive Differential Analysis of RNA-Seq Data," PLOS ONE, Public Library of Science, vol. 11(6), pages 1-8, June.
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