Kozicz, Tamas

Morava, Eva

Rahman, Shamima

UCL Discovery

The doxycycline paradox in primary mitochondrial diseases Tamas Kozicz1,,2,#, Shamima Rahman3,# and Eva Morava1,2,# 1Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA 2University of Pécs Medical School, Pécs, Hungary 3 Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK  #Equal contribution  Primary mitochondrial diseases (PMDs) are heterogeneous disorders affecting mitochondrial structure, function and/or dynamics and may be caused by pathogenic variants in hundreds of nuclear or mitochondrial DNA encoded genes1; 2. PMDs cause pathologies involving virtually any organ and are frequently life-limiting in early life3; 4. There are no disease-modifying therapies for the vast majority of PMDs and current treatments are mostly symptomatic4; 5. The first multiprotein enzyme complex  of the oxidative phosphorylation system is complex I (CI). CI plays an essential role in generation of chemical energy and its deficiency is associated with a robust increase in reactive oxygen species (ROS) production leading to the development of various pathologies including Leigh syndrome6; 7.    Several mitochondrial functions can be traced back to their endosymbiotic ‘bacterial’ origin8. Consequently, antibiotics that target bacterial translation may also inhibit mitochondrial translation. Historically, some sources suggested avoiding certain antibiotics in patients with PMDs, especially antibiotics affecting translation including doxycycline. A recent Delphi consensus review however found no evidence base for this practice and so it is now discouraged9.  Interestingly, doxycycline extended lifespan of worms via increasing mitochondrial unfolded protein response and attenuating mitochondrial respiration10-12. Specifically, doxycycline dose-dependently reduced oxygen consumption, without affecting citrate synthase activity or ATP levels10. Given at a low concentration during development, doxycycline did not appear to cause any adverse effects10.  This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as doi:10.1002/jimd.12531This article is protected by copyright. All rights reserved.Through a chemical high-throughput screen in cells derived from patients with PMD, Perry et al. also found that tetracycline analogues including doxycycline rescue cell death and inflammatory signatures through partial and selective inhibition of mitochondrial translation13. They also showed that doxycycline treatment strongly promotes fitness and survival of Ndufs4 knock-out mice, a model of Leigh syndrome14.   In contrast, Wüst et al. reported that mice treated with doxycycline presented with CI dysfunction and reduced mitochondrial respiratory capacity and concluded that doxycycline impairs mitochondrial function15. This may not be surprising since antibiotics designed to target the prokaryotic ribosome are known to induce dysregulation of mitochondrial function16.  Considering the above observations, doxycycline as a potential drug-targeted therapy for mitochondrial disease is highly paradoxical. So how can one reconcile the seemingly contradictory reports on the beneficiary effects of doxycycline versus its inhibitory action on mitochondrial translation and function?  To solve this paradox, one has to consider the different doses of doxycycline used in the two studies, which are not directly comparable. Another consideration is that doxycycline triggers a metabolic remodeling primarily driven by changes in the fatty acid oxidation pathway, suggesting a switch to lipid breakdown to fuel energy production10. Thus, doxycycline induces a metabolic rewiring favoring lipid metabolism12. It has also been proposed that in CI deficiencies the activity of CII (succinate dehydrogenase) is significantly upregulated17. Increased CII activity as an adaptive response to CI improves lipid oxidation and provides a high rate of ATP18.  The major electron donor for CI is NADH and FADH2 for CII. The ratio of NADH versus FADH2 oxidation depends on the proton motive force, and lowering proton motive force by e.g., inhibiting complex I by doxycycline will favor FADH2 oxidation, i.e., towards using lipids versus carbohydrate as fuel source.   We propose a mechanism to explain the potential beneficiary effects of doxycycline in individuals with PMDs, especially with CI-related PMD. As doxycycline decreases CI activity, the accompanying metabolic rewiring favors CII driven fatty acid oxidation and provides a sufficient rate of ATP production to ameliorate symptoms. One has to consider too that this beneficiary effect of doxycycline could be dose dependent.  In summary, doxycycline is another example, along with rapamycin and hypoxia19; 20, showing that CI activity is not required to rescue pathologies associated with PMDs. Currently, there are no clinically effective therapies for PMDs, and the above findings suggest that tetracyclines might constitute a potential intervention to ameliorate symptoms for PMDs. Further studies are warranted, including clinical trials if additional preclinical data suggest a beneficial effect of doxycycline.  References 1. Wallace, D.C., and Chalkia, D. (2013). Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol 5, a021220. 2. Rahman, J., and Rahman, S. (2018). Mitochondrial medicine in the omics era. The Lancet 391, 2560-2574. 3. Gorman, G.S., Chinnery, P.F., DiMauro, S., Hirano, M., Koga, Y., McFarland, R., Suomalainen, A., Thorburn, D.R., Zeviani, M., and Turnbull, D.M. (2016). Mitochondrial diseases. Nature reviews Disease primers 2, 1-22. 4. Russell, O.M., Gorman, G.S., Lightowlers, R.N., and Turnbull, D.M. (2020). Mitochondrial Diseases: Hope for the Future. Cell 181, 168-188. 5. Pitceathly, R.D.S., Keshavan, N., Rahman, J., and Rahman, S. (2021). Moving towards clinical trials for mitochondrial diseases. J Inherit Metab Dis 44, 22-41. 6. Koopman, W.J., Willems, P.H., and Smeitink, J.A. (2012). Monogenic mitochondrial disorders. N Engl J Med 366, 1132-1141. 7. Abramov, A.Y., and Angelova, P.R. (2019). Cellular mechanisms of complex I-associated pathology. Biochem Soc Trans 47, 1963-1969. 8. Margulis, L. (1975). Symbiotic theory of the origin of eukaryotic organelles; criteria for proof. Symp Soc Exp Biol, 21-38. 9. De Vries, M.C., Brown, D.A., Allen, M.E., Bindoff, L., Gorman, G.S., Karaa, A., Keshavan, N., Lamperti, C., McFarland, R., Ng, Y.S., et al. (2020). Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus. J Inherit Metab Dis 43, 800-818. 10. Houtkooper, R.H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., Williams, R.W., and Auwerx, J. (2013). Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451-457. 11. Zhu, L., Zhou, Q., He, L., and Chen, L. (2021). Mitochondrial unfolded protein response: An emerging pathway in human diseases. Free Radic Biol Med 163, 125-134. 12. Gao, A.W., El Alam, G., Lalou, A., Li, T.Y., Molenaars, M., Zhu, Y., Overmyer, K.A., Shishkova, E., Hof, K., Bou Sleiman, M., et al. (2022). Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains. iScience 25, 103734. 13. 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The doxycycline paradox in primary mitochondrial diseases

https://discovery.ucl.ac.uk/id/eprint/10151270/

The doxycycline paradox in primary mitochondrial diseases

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