Friday, November 22, 2024
11/22/2024
Rapamycin is an inhibitor of the mechanistic Target of Rapamycin pathway (mTOR). This drug has anti-carcinogenic and pro-longevity characteristics. We, and others, have shown that rapamycin could also be considered as a treatment for mitochondrial disorders since feeding rapamycin to genetic models for mitochondrial disorders improve the pathology associated with the diseases. However, resistance to rapamycin hinders the efficacy of such treatment. Molecular genetic analysis in D. melanogaster provides unique approaches to uncover the basic mechanism of insensitivity of rapamycin. In this context, we have discovered that introgressed strains of Drosophila harboring mitochondrial DNA form D. simulans in a D. melanogaster nuclear DNA do not respond to rapamycin treatment while wild type D. melanogaster or wild type D. simulans respond to the drug. In addition, we discovered that rapamycin beneficial effect on mitochondrial function requires a shift of metabolism, in particular, the catabolism of proteins. Wild type D. melanogaster fed a diet rich on proteins, or lacking proteins do not respond to the increase on metabolic rate mediated by rapamycin. Metabolomics analysis and preliminary molecular genetics analysis with mutants for the glutamate dehydrogenase, the enzyme that catabolize glutamate into alpha-ketoglutarate, have identified the critical role of the glutamine, glutamate and alpha-ketoglutarate anapleourotic (Gln-Glu-αKG) pathway in the response to rapamycin. Based on our observations and the documented effects of the sensitivity and the resistance to rapamycin, in this proposal we will test the hypothesis that rapamycin sensitivity depends upon the qualitative used of the Gln-Glu-αKG pathway by the cell. To test this hypothesis, we will use a combination of introgressed mitochondrial DNAs strains, with and without mutations on genes that codify for several members of the the Gln-Glu-αKG pathway. We will study the sensitivity and resistance to rapamycin treatment by exposing the aforementioned strains to rapamycin treatment in the presence and absence of amino acids supplementation. We will complement those analyses with metabolomics assays that will depict the metabolic space of the resistance to rapamycin. Overall, this proposal aims to identified the hallmarks of the insensitivity to rapamycin treatment using a unique set of tools provided with the use of mitochondria introgressed strains.
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