Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL, Gower Street, London, WC1E 6BT, UK.
UCL Cancer Institute, 72 Huntley St, London, WC1E 6DD, UK.
Nat Commun. 2021 Nov 4;12(1):6409. doi: 10.1038/s41467-021-26746-2.
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.
线粒体基因组 (mtDNA) 的突变会导致一系列严重的临床疾病，而这些疾病的治疗选择非常有限。大多数 mtDNA 疾病表现出异质性 - 组织同时表达野生型和突变型 mtDNA。虽然异质性水平与疾病严重程度广泛相关，但特定的 mtDNA 突变、异质性、疾病表型和严重程度之间的关系尚未得到很好的理解。我们对携带最常见疾病相关 mtDNA 突变（m.3243A>G）的异质患者来源细胞进行了广泛的生物能量学、代谢组学和 RNAseq 研究。这些研究表明，该突变促进了代谢物的变化，这些变化与患者来源细胞和组织中 PI3K-Akt-mTORC1 轴的上调有关。值得注意的是，PI3K、Akt 或 mTORC1 的药理学抑制降低了 mtDNA 突变体负荷，并部分挽救了细胞的生物能量功能。因此，PI3K-Akt-mTORC1 轴代表了一个潜在的治疗靶点，可能有益于患有 m.3243A>G 突变的人。
