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Autophagy, Feb 26 2024, | https://doi.org/10.1080/15548627.2024.2323785 Sodium butyrate ameliorates high glucose-suppressed neuronal mitophagy by restoring PRKN expression via inhibiting the RELA-HDAC8 complex

Ji Hyeon Cho ^1,†, Chang Woo Chae ^1,†, Jae Ryong Lim ¹, Young Hyun Jung ¹, Su Jong Han ¹, Jee Hyeon Yoon ¹, Ji Yong Park ¹, Ho Jae Han ^1,*

¹Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, BK21 FOUR Future Veterinary Medicine Leading Education and Researchma Center, Seoul National University, Seoul, South Korea.

^†These authors contributed equally
^*Corresponding author: correspondence to Ho Jae Han

Abstract

Damaged mitochondria accumulation in diabetes is one of the main features that contribute to increased incidence of cognitive impairment by inducing apoptosis. Butyrate is a major metabolite produced by microbiota that has neuroprotective effects by regulating mitochondrial function. However, detailed mechanisms underlying how butyrate can regulate neuronal mitophagy remain unclear. Here, we examined the regulatory effects of sodium butyrate (NaB) on high glucose-induced mitophagy dysregulation, neuronal apoptosis, and cognitive impairment and its underlying mechanisms in human-induced pluripotent stem cell-derived neurons, SH-SY5Ys, and streptozotocin (STZ)-induced diabetic mice. In our results, diabetic mice showed gut-microbiota dysbiosis, especially a decreased number of butyrate-producing bacteria and reduced NaB plasma concentration. NaB ameliorated high glucose-induced neuronal mitochondrial dysfunction by recovering PRKN/Parkin-mediated mitophagy. High glucose-induced reactive oxygen species (ROS) and -inhibited PRKAA/AMPKα stimulated the RELA/p65-HDAC8 complex, which downregulated PRKN protein expression by binding to the PRKN promoter region. NaB restored PRKN expression by blocking RELA nuclear translocation and directly inhibiting HDAC8 in the nucleus. In addition, HDAC8 overexpression inhibited the positive effect of NaB on high glucose-induced mitophagy dysfunction and neuronal apoptosis. Oral administration of NaB improved cognitive impairment in diabetic mice by restoring mitophagy in the hippocampus. Taken together, NaB ameliorates neuronal mitophagy through PRKN restoration by inhibiting RELA-HDAC8 complexes, suggesting that NaB is an important substance for protecting neuronal apoptosis in diabetes-associated cognitive impairment.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-20)
연구진국내 연구진
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