MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease.

Abstract

Primary genetic mitochondrial diseases (GMDs) are clinically and genetically diverse diseases. Leigh syndrome (LS), the most common pediatric presentation of GMD is a severe progressive multi-system disorder with diverse manifestations. No effective treatments currently exist. Recent data from the Ndufs4(-/-) LS mouse model show that peripheral macrophages contribute to brain lesions, that disease is driven by innate immune populations and that depletion of innate immune cells prevents disease. However, the mechanisms underlying the immune activation in LS remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and DNA are detected by toll-like receptors (TLRs) at the endosome and may mediate innate immune activation in LS. To assess TLR signaling in an LS mouse model, we generated TLR signaling-deficient Ndufs4(-/-)/MyD88(-/-) animals. Prophylactic antibiotic treatment with enrofloxacin enabled production of MyD88(-/-) animals from Ndufs4(+/-)/MyD88(+/-) breeder pairs. Loss of MyD88 in Ndufs4(-/-) animals increased survival and delayed the onset but disease courses were not altered. We conclude that Myd88-mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of MyD88(-/-) animals modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in mitochondrial diseases warrants further investigation.