Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions

Hideji Yako,Koichi Kato,Kazunori Sango,Ayako Kato,Shizuka Takaku,Yasuaki Tatsumi,Yasumasa Nishito,Naoko Niimi

doi:10.1038/s41598-021-98082-w

Hideji Yako, Koichi Kato + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-98082-w

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Abstract

Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis–TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.

Highlights

Pyruvate functions as a key molecule in energy production and as an antioxidant
We observed that the absence of exogenous pyruvate under high-glucose conditions induces time and glucose concentration-dependent cell death of immortalized mouse Schwann cells (IMS32), as well as primary cultured rat dorsal root ganglion (DRG) neurons, lined mouse motor neurons (NSC-34), mesangial cells (MES13), and human aortic endothelial cells (HAECs)
Several studies showed the efficacy of pyruvate supplementation in diabetes and its complications by employing experimental diabetic a nimals[4,5,6], the critical role of exogenous pyruvate in survival and energy production in various cell types during exposure to high-glucose has not yet been documented and we believe these findings are novel and biologically significant

Summary

Introduction

The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. Targeted gene disruption of murine pyruvate kinase, which catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, was shown to exacerbate diabetic nephropathy[7] These findings suggest that both endogenous and exogenous pyruvate prevent and ameliorate diabetes and its complications. Significant depletion of glycolytic and tricarboxylic acid (TCA) cycle intermediates in the peripheral nerves of diabetic mice was previously reported[9,10] These findings led us to speculate that exogenous pyruvate could restore the impaired glycolysis–TCA cycle flux in the PNS under diabetic conditions.

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