Rapamycin Use Increased Lifespan in Leigh Syndrome Animal Models

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Leigh syndrome and Rapamycin

Both mouse and fruit fly animal models of Leigh syndrome suggest that blocking a specific pathway controlled by the protein TOR increases animals’ lifespan. The results suggest that a future therapeutic strategy for Leigh syndrome, and possibly other mitochondria diseases, may require TOR inhibition.

The study, “Rapamycin enhances survival in a Drosophila model of mitochondrial disease,” was published in the journal Oncotarget.

Mitochondria dysfunction is the cause of a category of pediatric mitochondrial disorders, with Leigh syndrome being the most common. This syndrome is a rare, inherited neurometabolic disorder that affects the central nervous system. Symptoms typically arise during the first year after birth and progress rapidly until death, usually by 6-7 years of age.

Mutations  in mitochondria genes, specifically the genes encoding complex I assembly factor NDUFS4 and the mitochondrial-encoded ND2 subunit of complex I, are two of the causal mutations implicated in Leigh syndrome in children. In fact, studies in mice that lack NDUFS4 showed that mice are deficient for complex I activity and show many of the symptoms associated with Leigh syndrome, including retarded growth, necrotizing encephalopathy, and dramatically reduced lifespan.

NDUFS4 knockout mice, researchers found, exhibited hyperactivation of a signaling pathway controlled by a protein called TOR (Target Of Rapamycin) in the brain.

Recently, researchers showed that TOR signaling significantly rescued the shortened lifespan, neurological symptoms, and neurodegeneration in NDUFS4 KO mice, a mouse model of Leigh syndrome.

However, the mechanism by which TOR inhibition induces these positive outcomes in a mice model of Leigh syndrome remained unknown. Moreover, the possibility that these findings could extend to other models of mitochondrial deficiency required further research.

Researchers studied the effects of TOR inhibition in a Drosophila model (a member of fruit flies family and extensively used as a model organism to study several human diseases) of Leigh syndrome.

The team found that rapamycin-mediated TOR inhibition robustly extended the lifespan of this Drosophila model of Leigh syndrome, without affecting behavior features of Drosophila-Leigh syndrome previously observed in a mouse model for the disease.

Notably, researchers found that the increase in lifespan in response to TOR blocking may be due to metabolic changes. While the Drosophila model of Leigh syndrome showed reduced body weight and defects in fat storage and metabolism, all these symptoms were reversed by the drug rapamycin.

Preliminary results suggest that TOR blocking may be a potential therapeutic strategy in diseases arising from mitochondrial dysfunction.