Ketosis rescues frataxin deficiency and corrects disease phenotypes in an FRDA animal model

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by deficiency of the mitochondrial protein frataxin. Effective therapeutic options remain limited for FRDA. We previously demonstrated that frataxin regulates ketone body metabolism by modulating 3-Oxoacid CoA-Transferase 1 (OXCT1), the rate-limiting enzyme in ketone body catabolism. However, the mechanisms governing frataxin-dependent control of OXCT1 turnover as well as the contribution of frataxin deficiency-induced OXCT1 reduction to FRDA pathogenesis, have remained unclear. Here, we demonstrate that frataxin regulates OXCT1 protein turnover by inhibiting its ubiquitination and subsequent proteasomal degradation. The N-terminal 40 amino acids of frataxin mediate such events, as overexpression of this region alone blocks ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. To evaluate the impact of OXCT1 deficiency on FRDA phenotypes, we enhanced OXCT1 reduction by introducing a 50% OXCT1 knockout into frataxin-deficient KIKO mice (KIKO/OXCT1/-). While OXCT1 deficiency potentiates cell death in vitro in control and FRDA patient fibroblasts, further OXCT1 reduction in KIKO mice induces ketosis, increases frataxin levels, and improves neurobehavioral performance. The increase in frataxin does not reflect elevated FXN gene transcription but rather enhanced mitochondrial biogenesis, evidenced by increased biogenesis markers, restored mitochondrial morphology and size, and increased mitochondrial gene expression. Fasting-which promotes ketosis-similarly increases frataxin levels and mitochondrial biogenesis markers in older KIKO/OXCT1+/- mice. {beta}-hydroxybutyrate administration in FRDA iPSC-derived cardiomyocytes elevates frataxin levels and mitochondrial biogenesis markers, further supporting the beneficial effect of ketosis on frataxin expression and mitochondrial biogenesis. Collectively, our findings demonstrate that ketosis partially restores frataxin levels and ameliorates FRDA-related phenotypes, providing a potential therapeutic strategy for FRDA.