Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models

Abstract

Mitochondrial diseases (MD) are a heterogeneous group of disorders resulting from genetic mutations in nuclear or mitochondrial DNA (mtDNA) genes encoding for mitochondrial proteins 1,2. MD cause pathologies with severe tissue damage and ultimately death 3,4. There are no cures for MD and current treatments are only palliative 5–7. To search for new drug-targeted therapies, we designed a chemical high-throughput screen using cells carrying human MD mutations to identify small molecules that prevent cellular damage and death under nutrient stress conditions. Top hits in the screen were a series of antibiotics that maintain survival of different human MD mutant cells. A sub-library of tetracycline analogs, including doxycycline, rescued cell death and inflammatory signatures in mutant cells through partial and selective mitochondrial translation inhibition, causing a mitohormetic response that was ATF4 independent. Remarkably, doxycycline treatment strongly promoted fitness and survival of Ndufs4-/- mice, a pre-clinical Leigh syndrome mouse model 8. Brain proteomic analysis showed that doxycycline treatment largely prevented neuronal death and the increases of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causality of these proteins in this brain pathology. These findings implicate tetracyclines as a potential therapeutic treatment for MD.