Metabolic treatment of neurological mitochondrial disorders

Project Summary
Inhibition of the mechanistic Target of Rapamycin (mTOR) improves prognosis in a mouse model of Leigh
Syndrome (LS) and in a small cohort of Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke
(MELAS) patients, two neurological mitochondrial disorders. However, its specific mechanism of action
remains to be determined. We find that the mTOR inhibitor rapamycin reverses metabolic alterations in LS
mice lacking the Complex I subunit Ndufs4 (Ndufs4-/-): more specifically, rapamycin reduces the accumulation
of glycolytic intermediates and increases the abundance of fatty acids in both brain and liver of Ndufs4-/- mice.
Loss of the mitochondrial sirtuin Sirt3 abrogates lifespan extension and the delay of neurological phenotypes in
Ndufs4-/- mice treated with rapamycin. In Aim 1 of this proposal, we explore the dependency of mTOR
inhibition on Sirt3 to improve disease phenotypes in these animals. Specifically, we hypothesize that
expression of Sirt3 in the liver is required to promote the metabolic shift to fatty acid oxidation described above.
Treatment with the Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI) Adefovir Dipivoxil (ADV) delays
symptoms of disease and improves survival in Ndufs4-/- mice. ADV increases the expression of C/EBP-β, a
transcription factor that increases hepatic fatty acid oxidation in response to calorie restriction and mTOR
inhibition. In Aim 2 we explore the hypothesis that C/EBP-β guides the metabolic shift induced by rapamycin in
Ndufs4-/- mice.
With a combination of genetic and pharmacological approaches, both aims will determine the exact nature of
the metabolic alterations induced by loss of Complex I, the mechanisms by which this loss of metabolic
homeostasis is rescued, and its importance in the etiology and progression of neurological mitochondrial
disease. This project will determine the metabolic nature of these disorders and lay the foundation for novel
treatments based on fine tuning of nutrient metabolism in patients affected by Complex I dysfunction.

Grant Number: 5R21NS136915-02
NIH Institute/Center: NIH
Principal Investigator: Alessandro Bitto