Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreich's 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.
More...Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreich's 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.
Overall design: The transcriptional profile of the cerebellum in frataxin-deficient (KIKO) mice was compared to that of wild-type (WT) mice at the bulk and single-cell level.
Less...| Accession | PRJNA1088162; GEO: GSE261655 |
| Type | Umbrella project |
| Publications | Sciarretta F et al., "Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism.", Life Sci Alliance, 2024 Jul;7(7) |
| Submission | Registration date: 14-Mar-2024
Physiology and Metabolism, Biology, Tor Vergata University |
| Relevance | Superseries |
Project Data:
| Resource Name | Number
of Links |
|---|
| Sequence data |
| SRA Experiments | 8 |
| Publications |
| PubMed | 1 |
| PMC | 1 |
| Other datasets |
| BioSample | 8 |
| GEO DataSets | 3 |
Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia encompasses the following 2 sub-projects:
| Project Type | Number of Projects |
| Transcriptome or Gene expression | 2 |
BioProject
accession | Organism | Title |
|---|
| PRJNA1088166 | Mus musculus | Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia (scRNA-Seq) (Physiology and Metabolism,...) | | PRJNA1088167 | Mus musculus | Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia (bulk RNA-Seq) (Physiology and Metabolism,...) |
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