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.
Highlights
Mutations of the mitochondrial genome cause a range of profoundly debilitating clinical conditions for which treatment options are very limited
A > G mutation, we used six cell lines: fibroblasts derived from two patients carrying the mutation, two controls matched for age and gender, an A549 cybrid cell line carrying the mutation and its wild-type (WT) counterpart
The distribution of mutant load in the cybrid cells ranged from 50–80%, showing a Gaussian distribution (Supplementary Fig. 7d). We found that this technique is less accurate than allele refractory mutation system (ARMS)-quantitative PCR (qPCR) and tends to overestimate the mutant load when it is lower than 50% and underestimate the mutant load when it is higher than 50%, the average single-cell mutant load was consistent with that of the whole cell population, suggesting a good precision of the technique
Summary
Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. We have found that the basal expression and activity of the PI3K-Akt-mTORC1 pathway were increased in the mutant cells, and were strongly associated with redox imbalance, oxidative stress, and glucose dependence.
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