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 (Area-Gomez and Schon, 2014; Wallace and Chalkia, 2013). MD cause pathologies with severe tissue damage and ultimately death (El-Hattab et al., 2015; Gorman et al., 2016). There are no cures for MD and current treatments are only palliative (El-Hattab et al., 2017; Pfeffer et al., 2012; Russell et al., 2020). 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 (Kruse et al., 2008). 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 strongly implicate tetracyclines as a potential therapeutic treatment for MD.