Nicotinamide riboside reduces glial inflammation and boosts mitochondrial function.

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Cellular Pathology

Background:

• Astrocyte dysfunction is central to POLG-related mitochondrial diseases, but mechanisms are unclear.
• Understanding astrocyte-mediated neurotoxicity is crucial for developing treatments.

Purpose of the Study:

• To model POLG mutations using human iPSC-derived astrocytes and organoids.
• To investigate astrocyte-mediated neurotoxicity and explore therapeutic interventions.

Main Methods:

• Utilized human induced pluripotent stem cell (iPSC)-derived astrocytes, cortical organoids, and astrocyte-neuron co-cultures.
• Performed single-cell transcriptomic profiling to analyze cellular changes.
• Assessed the impact of nicotinamide riboside (NR) treatment on cellular and molecular markers.

Main Results:

• POLG organoids showed increased A1 neurotoxic astrocytes, decreased A2 neuroprotective astrocytes, and neuronal loss.
• A1 astrocytes displayed mitochondrial dysfunction, inflammation, senescence, and impaired neuro-supportive functions.
• NR treatment reduced astrocyte reactivity, inflammation, improved neuronal integrity, and enhanced mitochondrial function (mtDNA copy number, ATP production).

Conclusions:

• Astrocyte dysfunction, particularly the expansion of A1 astrocytes, drives neurotoxicity in POLG-related mitochondrial diseases.
• NAD+ augmentation via NR represents a potential therapeutic strategy for these debilitating conditions.