RT Journal Article
SR Electronic
T1 Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243A>G mtDNA mutation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.18.159103
DO 10.1101/2020.06.18.159103
A1 Chih-Yao Chung
A1 Kritarth Singh
A1 Vassilios N Kotiadis
A1 Gabriel E Valdebenito
A1 Jee Hwan Ahn
A1 Emilie Topley
A1 Joycelyn Tan
A1 William D Andrews
A1 Benoit Bilanges
A1 Robert D S Pitceathly
A1 Gyorgy Szabadkai
A1 Mariia Yuneva
A1 Michael R Duchen
YR 2021
UL http://biorxiv.org/content/early/2021/06/14/2020.06.18.159103.abstract
AB 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, m.3243A>G. These studies reveal that the mutation promotes changes in metabolites which is associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 activated mitophagy, reduced mtDNA mutant load and rescued cellular bioenergetic function. The rescue was prevented by inhibition of mitophagy. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243A>G mutation.Competing Interest StatementThe authors have declared no competing interest.