Is the PI3K-AKT-MTORC1 signalling pathway a therapeutic target in mitochondrial diseases?

In cells from patients suffering from mitochondrial myopathy and carrying the m.3243A>G mutationModification soudaine et transmissible du matériel génétique. Elle peut être spontanée ou induite par des agents dits » mutagènes » (radiations, produits toxiques,…). in the MT-TL1 mitochondrial gene, in which the PI3K-AKT-MTORC1 signalling pathway is abnormally activated, researchers looked at the effects of inhibiting this signalling pathway (with rapamycin, LY294002, etc.) and showed :

• restoration of mitophagy and a reduction in mutational load ;
• signs of improvement in mitochondrial function: increase in mitochondrial membrane potential, improved oxidative phosphorylation, improvement in mitochondrial function preceding the reduction in mutational load.

These results indicate that the PI3K-AKT-MTORC1 pathway plays a role in mitochondrial metabolism and that oxidative phosphorylation is essential for the activation of mitophagy, the presence of pathogenic mitochondrial DNAmacromolécule complexe, l’ADN est le support de l’hérédité (gènes). C’est le constituant des chromosomes. L’ADN est organisé en double hélice (deux brins complémentaires) et constitué de nucléotides de quatre types : adénine, guanine, cytosine et thymine. alone not being sufficient to trigger selection against mutation by mitophagy.

Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function. Chung, C.-Y., Singh, K., Sheshadri, P. et al. Autophagy 2024 : 1-16.