Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Sciarretta, F.; Zaccaria, F.; Ninni, A.; Ceci, V.; Turchi, R.; Apolloni, S.; Chiurchiu, V.; Tiberi, M.; D'Ambrosi, N.; Pedretti, S.; Mitro, N.; AQUILANO, K.; Lettieri Barbato, D.; Della Valle, I.; Milani, M.

doi:10.1101/2023.10.18.562916

bioRxiv · 10.1101/2023.10.18.562916

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Sciarretta, F.·Zaccaria, F.·Ninni, A.·Ceci, V.·Turchi, R.·Apolloni, S.·Chiurchiu, V.·Tiberi, M.·D'Ambrosi, N.·Pedretti, S.·Mitro, N.·AQUILANO, K.·Lettieri Barbato, D.·Della Valle, I.·Milani, M.

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Abstract

Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreichs ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies. Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

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Sciarretta, F., Zaccaria, F., Ninni, A., Ceci, V., Turchi, R., Apolloni, S., Chiurchiu, V., Tiberi, M., D'Ambrosi, N., Pedretti, S., Mitro, N., AQUILANO, K., Lettieri Barbato, D., Della Valle, I., Milani, M.. 2023-10-20. Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia. https://doi.org/10.1101/2023.10.18.562916

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