The role of mTOR in mitochondrial disease

Abstract

Genetic mitochondrial diseases (GMD) impact over 1:4,000 live births and are a common underlying cause in both inherited metabolic disorders and inherited neurological diseases. No effective treatments exist for GMDs, and the mechanisms linking the primary genetic defects to pathology are unknown. Inhibition of the mechanistic target of rapamycin (mTOR), a master intracellular nutrient sensing-signaling kinase complex, with rapamycin significantly attenuates disease in multiple GMD models. In particular, rapamycin treatment attenuates neurodegeneration, metabolic dysfunction, and significantly extends survival of the Ndufs4(KO) mouse model of Leigh syndrome (LS), the most common pediatric presentation of GMD. Factors mediating the benefits of mTOR inhibition have previously been unknown. Studies targeting discrete pathways downstream of mTOR Ndufs4(KO) mouse have not recapitulated the effects of rapamycin treatment. The role of mTOR in metabolism is highly pleiotropic, and mTOR inhibition produces significant metabolic changes in the Ndufs4(KO) mouse that could mediate the benefits of rapamycin. Conversely, upstream signaling and cell-specific mTOR activity may define the role of mTOR in disease. In this work we reveal a novel model for the role of mTOR signaling in LS, representing a potential avenue for clinical therapy development, and explore the relationship between mTOR, metabolism, and mitochondrial disease. First, we determined that PI3Kγ-mTOR signaling participates in leukocyte proliferation, neuroinflammation, and disease in the Ndufs4(KO) mouse, and that pharmacological depletion of leukocytes robustly prevents disease in the Ndufs4(KO) model. Thus, we believe LS has an mTOR-associated immunologic origin, which is amenable to pharmacological targeting. Second, we show that these immunologic interventions rescue both neurodegeneration and major metabolic sequelae of disease, indicating that mTOR-mediated immune processes disrupt metabolism in the Ndufs4(KO) mouse. Finally, we characterize the metabolic effects of mTOR inhibition in control and Ndufs4(KO) animals, finding that mTOR inhibition decreases glycolytic flux and significantly alters systemic glucose regulation. Given the known role of glucose metabolism in leukocyte function, these changes are expected to have secondary effects on immune proliferation. Taken together, our findings support a mechanistic role for the immune system in driving disease pathogenesis in LS, but also reveal metabolic changes resulting from mTOR inhibition which could play a role in attenuating disease either through direct effects or by contributing impaired leukocyte proliferation. Future research will further probe the causal relationship between mTOR, glucose metabolism, and immune activity in GMDs.