RT Journal Article
SR Electronic
T1 Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402609
DO 10.26508/lsa.202402609
VO 7
IS 7
A1 Sciarretta, Francesca
A1 Zaccaria, Fabio
A1 Ninni, Andrea
A1 Ceci, Veronica
A1 Turchi, Riccardo
A1 Apolloni, Savina
A1 Milani, Martina
A1 Della Valle, Ilaria
A1 Tiberi, Marta
A1 Chiurchiù, Valerio
A1 D’Ambrosi, Nadia
A1 Pedretti, Silvia
A1 Mitro, Nico
A1 Volontè, Cinzia
A1 Amadio, Susanna
A1 Aquilano, Katia
A1 Lettieri-Barbato, Daniele
YR 2024
UL http://www.life-science-alliance.org/content/7/7/e202402609.abstract
AB Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich’s ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA.All raw data that support the findings of this study are available from the lead contact upon reasonable request. scRNA-seq and bulk RNA-seq datasets produced in this study are available from gene expression omnibus (GEO) with accession number GSE261655.