Tetracyclines promote survival and fitness in mitochondrial disease models

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). Here we show that tetracyclines improve fitness of cultured MD cells and ameliorate disease in a mouse model of Leigh syndrome. To identify small molecules that prevent cellular damage and death under nutrient stress conditions, we conduct a chemical high-throughput screen with cells carrying human MD mutations and discover a series of antibiotics that maintain survival of various MD cells. We go on to show that a sub-library of tetracycline analogs, including doxycycline, rescues cell death and inflammatory signatures in mutant cells through partial and selective inhibition of mitochondrial translation, resulting in an ATF4-independent mitohormetic response. Doxycycline treatment strongly promotes fitness and survival of Ndufs4(−/−) mice, a pre-clinical Leigh syndrome mouse model (8). A proteomic analysis of brain tissue reveals that doxycycline treatment largely prevents neuronal death and the accumulation of neuroimmune and inflammatory proteins in Ndufs4(−/−) mice, indicating a potential causality of these proteins in the brain pathology. Our findings suggest that tetracyclines deserve further evaluation as a potential drugs for the treatment of MD.