Tetracyclines promote survival and fitness in mitochondrial disease models
- 18 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Metabolism
- Vol. 3 (1), 33-42
- https://doi.org/10.1038/s42255-020-00334-y
Abstract
Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from mutations in nuclear or mitochondrial DNA genes encoding mitochondrial proteins1,2. MDs cause pathologies with severe tissue damage and ultimately death3,4. There are no cures for MDs and current treatments are only palliative5,6,7. 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 subsequently show that a sub-library of tetracycline analogues, 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 preclinical Leigh syndrome mouse model8. 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 causal role for these proteins in the brain pathology. Our findings suggest that tetracyclines deserve further evaluation as potential drugs for the treatment of MDs.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIH RO1 DK089883-07 NIDDK)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (RO1 GM121452 NIGMS, F32 GM125243-01A1)
- U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIH F30 DE028206-01A1 NIDCR)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
- Human Frontier Science Program (LT-000033/2019-L)
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