Pyruvate Regulates Reactive Oxygen Species (ROS) Production, Dysfunction and Aberrant Metabolism of Mitochondria in Fibroblast-like Synoviocytes of Rheumatoid Arthritis

Jeong Yeon Kim^1,2, Shin Eui Kang^2,3, Hyun Jung Yoo^3,4, Ji Soo Park¹, Eun Young Lee², Eun Bong Lee² and Yeong Wook Song^3,4, ¹Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea, The Republic of, ²Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, The Republic of, ³Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea, ⁴Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Metabolism, mitochondria and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 15, 2016

Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis - Poster III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: In rheumatoid arthritis (RA), fibroblast-like synoviocyte (FLS) is a key component of invasive synovium and mediates inflammation and destruction of joint. Recently, change of metabolic pathways offers novel approach to understanding the inflammation in RA. However, it has remained unknown how mitochondrial metabolic profiles are associated with inflammation in RA. In addition, production of reactive oxygen species (ROS), formed as byproduct in metabolic pathway is reported to be attenuated by pyruvate supplement in in vitro study. This study aimed to evaluate mitochondrial ROS signaling, biosynthetic functions and cytokine production, and the effects of pyruvate supplement in RA-FLS.

Methods: We analyzed mitochondrial ROS signaling and mitochondrial functions by quantitative PCR and western blotting in RA-FLS lysates. Mitochondrial metabolism was evaluated by mitochondrial respiration using a Seahorse Bioscience Extracellular Flux Analyzer (XF24). The oxidative damage and biogenesis in mitochondria was evaluated by transmission electron microscopy (TEM) and western blotting in RA-FLS. IL-6 was measured by ELISA.

Results: Generation of TNF-α-induced mitochondrial ROS was higher in the FLS from RA patients compared to patients with osteoarthritis (OA). Peroxiredoxin 3 (Prx3), mitochondrial specific H₂O₂-scavenging enzyme, was significantly decreased in the TNF-a stimulated RA-FLS at early time (p=0.019). In addition, we showed increased mitochondrial respiration (p<0.00001), dysfunction of mitochondria and mitophagy including up-regulation of p62 and LC3B in the RA-FLS compared with OA-FLS. These mitochondrial phenotypes of RA-FLS were attenuated by treatment of pyruvate in TEM and western blot analysis. In addition, pyruvate supplement decreased IL-6 release in the TNF-a stimulated RA-FLS.

Conclusion: Pyruvate may act as a new therapeutic metabolite for improvement of mitochondrial dysfunction and proinflammatory cytokine production in RA-FLS.

Disclosure: J. Y. Kim, None; S. E. Kang, None; H. J. Yoo, None; J. S. Park, None; E. Y. Lee, None; E. B. Lee, None; Y. W. Song, None.

To cite this abstract in AMA style:

Kim JY, Kang SE, Yoo HJ, Park JS, Lee EY, Lee EB, Song YW. Pyruvate Regulates Reactive Oxygen Species (ROS) Production, Dysfunction and Aberrant Metabolism of Mitochondria in Fibroblast-like Synoviocytes of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/pyruvate-regulates-reactive-oxygen-species-ros-production-dysfunction-and-aberrant-metabolism-of-mitochondria-in-fibroblast-like-synoviocytes-of-rheumatoid-arthritis/. Accessed .

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