Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis


Hyperglycemia in diabetes mellitus (DM) patients is a causative factor for amyloidogenesis and induces neuropathological changes, such as impaired neuronal integrity, neurodegeneration, and cognitive impairment. Regulation of mitochondrial calcium influx from the endoplasmic reticulum (ER) is considered a promising strategy for the prevention of mitochondrial ROS (mtROS) accumulation that occurs in the Alzheimer’s disease (AD)-associated pathogenesis in DM patients. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A has received an increasing amount of attention as a novel candidate with anti-oxidative and neuroprotective effects in AD. Here, we investigated the effect of urolithin A on high glucose-induced amyloidogenesis caused by mitochondrial calcium dysregulation and mtROS accumulation resulting in neuronal degeneration. We also identified the mechanism related to mitochondria-associated ER membrane (MAM) formation. We found that urolithin A-lowered mitochondrial calcium influx significantly alleviated high glucose-induced mtROS accumulation and expression of amyloid beta (Aβ)-producing enzymes, such as amyloid precursor protein (APP) and β-secretase-1 (BACE1), as well as Aβ production. Urolithin A injections in a streptozotocin (STZ)-induced diabetic mouse model alleviated APP and BACE1 expressions, Tau phosphorylation, Aβ deposition, and cognitive impairment. In addition, high glucose stimulated MAM formation and transglutaminase type 2 (TGM2) expression. We first discovered that urolithin A significantly reduced high glucose-induced TGM2 expression. In addition, disruption of the AIP–AhR complex was involved in urolithin A-mediated suppression of high glucose-induced TGM2 expression. Markedly, TGM2 silencing inhibited inositol 1, 4, 5-trisphosphate receptor type 1 (IP3R1)–voltage-dependent anion-selective channel protein 1 (VDAC1) interactions and prevented high glucose-induced mitochondrial calcium influx and mtROS accumulation. We also found that urolithin A or TGM2 silencing prevented Aβ-induced mitochondrial calcium influx, mtROS accumulation, Tau phosphorylation, and cell death in neuronal cells. In conclusion, we suggest that urolithin A is a promising candidate for the development of therapies to prevent DM-associated AD pathogenesis by reducing TGM2-dependent MAM formation and maintaining mitochondrial calcium and ROS homeostasis.

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Fig. 1: Effect of urolithins on mitochondrial calcium, ROS in neuronal cells under high glucose condition.
Fig. 2: Effect of urolithin A on amyloidogenesis in neuronal cells under high glucose condition.
Fig. 3: Effect of urolithin A in MAM-regulated mitochondrial calcium under high glucose condition.
Fig. 4: Role of TGM2 in high glucose-induced MAM formation and amyloidogenesis.
Fig. 5: Effect of urolithin A on inhibition of TGM2 expression via formation of AIP–AhR transcriptomal complex.
Fig. 6: Protective effects of urolithin A on Aβ-induced mitochondrial calcium influx, mtROS accumulation, and neuronal cell death.
Fig. 7: Role of TGM2 in Aβ-induced mitochondrial calcium overload, mtROS accumulation, tau phosphorylation, and neuronal cell death.
Fig. 8: The schematic model for action mechanism of urolithin A on high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium influx.


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This research was supported by National R&D Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2020R1A2B5B02002442, NRF-2018R1D1A1B07050212) and BK21 PLUS Program for Creative Veterinary Science Research.

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HJL: Conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing. YHJ: Conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing. GEC, JSK, CWC, JRL, SYK, and JHY: Collection of data. SJL: Data analysis and interpretation, manuscript writing. HJH: Conception and design, data analysis and interpretation, and manuscript writing.

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Correspondence to Ho Jae Han.

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Lee, H.J., Jung, Y.H., Choi, G.E. et al. Urolithin A suppresses high glucose-induced neuronal amyloidogenesis by modulating TGM2-dependent ER-mitochondria contacts and calcium homeostasis. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-0593-1

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