Damaged mitochondria accumulation of neurons and abnormal gut microbiota composition in diabetes are considered a risk factor for the increased incidence of cognitive impairment, but the molecular basis for this has remained largely unknown. Korean researchers at Seoul National University report the discovery of molecular mechanisms underlying the regulatory effects of butyrate, microbiome metabolites, on high glucose-induced mitophagy dysregulation, neuronal apoptosis, and cognitive impairment. The study appears in the journal Autophagy. 

Mitophagy, which selectively removes damaged mitochondria through the autophagy/lysosomal pathway, is essential for proper mitochondrial function by maintaining mitochondrial quality control. This study worked by the researchers, led by Ho jae Han, found that butyrate ameliorates high glucose-induced damaged mitochondria accumulation in neurons by restoring parkin-mediated mitophagy. Furthermore, they found that butyrate restores parkin expression by interfering with the RELA-HDAC8 complex induced by high glucose.

Recently, several studies have reported the imbalance in the intestinal microbiome that is associated with diabetes causes gut-brain axis disturbances, which may significantly contribute to the pathogenesis of cognitive impairment. Prof. Han said that “we showed for the first time the protective effect of butyrate on diabetes-associated cognitive impairment through mitophagy regulation”. He also suggests that “microbiota-derived butyrate will help understand and diagnose the causes of diabetes-associated cognitive impairment, and is expected to lay the foundation for the development of new potential therapeutic candidates”.

The protective effect of butyrate against high glucose-suppressed parkin-dependent mitophagy that leads to cognitive impairment. 

[Reference] 

1. Cho JH, Chae CW. et al., (2024) “Sodium butyrate ameliorates high glucose-suppressed neuronal mitophagy by restoring PRKN expression via inhibiting the RELA-HDAC8 complex” Autophagy 
doi: 10.1080/15548627.2024.2323785
2. Chae CW. et al., (2023) “TRIM16-mediated lysophagy suppresses high-glucose-accumulated neuronal Aβ” Autophagy. doi: 10.1080/15548627.2023.2229659

3. Kim SY et al., (2020) “Sodium butyrate inhibits high cholesterol-induced neuronal amyloidogenesis by modulating NRF2 stabilization-mediated ROS levels: involvement of NOX2 and SOD1” Cell Death Dis. doi: 10.1038/s41419-020-2663-1

[Main Author] 

Ji Hyeon Cho (Seoul National University), Chang Woo Chae (Seoul National University)

* Contact email : Professor Ho Jae Han (hjhan@snu.ac.kr)