Frataxin Deficiency Leads to Metabolic Shift and Inflammatory Activation in Cerebellar Microglia

المفاهيم الأساسية

Frataxin deficiency in microglia triggers a metabolic shift from mitochondrial oxidation to glycolysis, leading to an inflammatory phenotype that can be mitigated by the short-chain fatty acid butyrate through the itaconate-Nrf2-GSH pathway.

الملخص

This study investigates the effects of frataxin (FXN) deficiency, which causes Friedreich's ataxia (FRDA), on the metabolic and inflammatory profiles of cerebellar microglia. Using single-cell RNA sequencing, the researchers identified an inflammatory microglial response in the cerebellum of a FRDA mouse model.
Further analysis revealed that FXN-deficient microglia exhibit enhanced glycolysis and itaconate production, potentially driving the inflammatory phenotype. Metabolomic studies showed that FXN-deficient microglia had increased glucose uptake, glycolytic metabolites, and lactate production, while mitochondrial metabolites remained unchanged.
The researchers found that the mitochondrial metabolite itaconate, which is produced in response to inflammation, helped mitigate the inflammatory response in FXN-deficient microglia by activating the Nrf2-mediated antioxidant pathway and limiting glycolysis.
Importantly, the short-chain fatty acid butyrate was able to further enhance itaconate levels, promote Nrf2 nuclear translocation, and increase glutathione (GSH) levels in FXN-deficient microglia. This led to the dampening of inflammatory gene expression and NF-κB signaling. In vivo experiments in FRDA mice showed that dietary butyrate supplementation improved neuromotor performance, likely by reducing neuroinflammation.
The study highlights the key role of metabolic reprogramming in driving microglial inflammation in FRDA and identifies butyrate as a potential therapeutic agent that can restore the immunometabolic balance and alleviate neuroinflammation.

الإحصائيات

Glucose uptake was significantly increased in FXN-deficient microglia compared to controls.
Glycolytic and pentose phosphate pathway metabolites were significantly elevated in FXN-deficient microglia.
Lactate production was significantly higher in FXN-deficient microglia.
Itaconate levels were significantly increased in FXN-deficient microglia.
Butyrate treatment reduced glucose uptake, lactate production, and increased mitochondrial metabolites in FXN-deficient microglia.

اقتباسات

"FXN deficiency forces glycolytic catabolism promoting inflammatory phenotype in microglial cells."
"Itaconate overproduction observed in FXN-deficient microglia cells was in accordance with the increased expression levels the immune-responsive gene 1 (Irg1)."
"Butyrate effectively restored the immunometabolic defects both in vitro and in vivo improving the neuromotor abilities in the FRDA mouse model."

الرؤى الأساسية المستخلصة من

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

by Sciarretta,F... في www.biorxiv.org 10-20-2023

https://www.biorxiv.org/content/10.1101/2023.10.18.562916v1

استفسارات أعمق

How might the metabolic reprogramming observed in FXN-deficient microglia impact other cell types in the cerebellum and contribute to the broader pathogenesis of Friedreich's ataxia?

The metabolic reprogramming observed in FXN-deficient microglia, characterized by a shift towards glycolysis and increased itaconate production, can have significant implications for other cell types in the cerebellum. Microglia, as the primary immune cells in the central nervous system, play a crucial role in maintaining homeostasis and responding to inflammatory stimuli. The heightened inflammatory phenotype in FXN-deficient microglia can lead to the release of pro-inflammatory cytokines and reactive oxygen species, impacting neighboring cells such as neurons, astrocytes, and oligodendrocytes.
Neurons are particularly vulnerable to neuroinflammation, and the dysregulated immune response from FXN-deficient microglia can contribute to neuronal damage and dysfunction. Astrocytes, which provide metabolic support and maintain the blood-brain barrier, may also be affected by the altered metabolic profile of microglia, leading to disruptions in neurotransmitter recycling and antioxidant defense mechanisms. Oligodendrocytes, responsible for myelination in the central nervous system, could experience impaired function due to the inflammatory environment created by FXN-deficient microglia.
Overall, the metabolic reprogramming in microglia can trigger a cascade of inflammatory responses and metabolic disturbances in other cell types within the cerebellum, exacerbating the pathogenesis of Friedreich's ataxia and contributing to the neurodegenerative processes observed in the disease.

How might other dietary or pharmacological interventions, beyond butyrate, potentially target the itaconate-Nrf2-GSH pathway to alleviate neuroinflammation in Friedreich's ataxia and similar neurodegenerative conditions?

In addition to butyrate, several other dietary or pharmacological interventions could target the itaconate-Nrf2-GSH pathway to alleviate neuroinflammation in Friedreich's ataxia and similar neurodegenerative conditions. Some potential interventions include:

Nrf2 Activators: Compounds that directly activate the Nrf2 pathway, such as sulforaphane from cruciferous vegetables or curcumin from turmeric, can enhance the antioxidant response and reduce inflammation in microglia. These natural compounds have been shown to upregulate Nrf2 target genes and promote GSH synthesis, offering neuroprotective effects in neurodegenerative disorders.

Itaconate Derivatives: Synthetic derivatives of itaconate with enhanced stability and bioavailability could be developed to specifically target the Nrf2-GSH pathway. These compounds could mimic the anti-inflammatory properties of itaconate and promote the activation of Nrf2 to counteract oxidative stress and inflammation in microglia.

GSH Precursors: Substances that serve as precursors for GSH synthesis, such as N-acetylcysteine (NAC) or alpha-lipoic acid, can boost cellular antioxidant defenses and support the Nrf2-mediated response. By increasing GSH levels, these compounds can mitigate neuroinflammation and protect against oxidative damage in neurodegenerative conditions.

Microbiome Modulators: Interventions that target the gut microbiome to promote the production of beneficial short-chain fatty acids, including butyrate, could indirectly influence the itaconate-Nrf2-GSH pathway. Probiotics, prebiotics, or dietary fibers that enhance the growth of butyrate-producing bacteria may improve gut-brain axis communication and reduce neuroinflammation in Friedreich's ataxia.

By exploring these alternative dietary or pharmacological interventions, researchers can uncover novel strategies to modulate the itaconate-Nrf2-GSH pathway and alleviate neuroinflammation in Friedreich's ataxia and related neurodegenerative disorders.

Given the complex interplay between the gut microbiome, short-chain fatty acids, and neuroinflammation, how might future research explore the gut-brain axis as a therapeutic avenue for Friedreich's ataxia and other neurodegenerative disorders?

Future research exploring the gut-brain axis as a therapeutic avenue for Friedreich's ataxia and other neurodegenerative disorders can focus on several key areas:

Microbiome Profiling: Conducting comprehensive microbiome profiling studies in individuals with Friedreich's ataxia to identify specific alterations in gut microbial composition associated with the disease. Understanding how these changes impact short-chain fatty acid production, immune modulation, and neuroinflammation can provide insights into potential therapeutic targets.

Prebiotic and Probiotic Interventions: Investigating the effects of prebiotics, probiotics, and synbiotics on gut microbiota composition and short-chain fatty acid production in preclinical and clinical models of Friedreich's ataxia. These interventions can modulate the gut microbiome to promote a healthy microbial ecosystem and enhance the production of beneficial metabolites with anti-inflammatory properties.

Short-Chain Fatty Acid Supplementation: Exploring the therapeutic potential of short-chain fatty acid supplementation, including butyrate, propionate, and acetate, in mitigating neuroinflammation and neurodegeneration in Friedreich's ataxia. Understanding the mechanisms by which these metabolites interact with the gut-brain axis and influence microglial function can inform targeted therapeutic strategies.

Clinical Trials: Designing clinical trials to evaluate the efficacy of gut microbiome-targeted interventions, such as fecal microbiota transplantation or dietary modifications, in individuals with Friedreich's ataxia. Assessing changes in neuroinflammation, disease progression, and neurobehavioral outcomes following gut microbiome modulation can provide valuable clinical insights.

By delving into the intricate connections between the gut microbiome, short-chain fatty acids, and neuroinflammation, future research can uncover novel therapeutic approaches that harness the gut-brain axis to address the underlying pathophysiology of Friedreich's ataxia and other neurodegenerative disorders.