2. Academic Validation
  3. 4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation

4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation

  • Biomolecules. 2022 Sep 4;12(9):1236. doi: 10.3390/biom12091236.
Jianmin Wu 1 2,  Xingshi Gu 1 2,  Juan Zhang 1 2,  Ze Mi 1 2,  Zhenhu He 1 2,  Yuqian Dong 1 2,  Wu Ge 1 2,  Kedar Ghimire 3,  Pengfei Rong 1 2,  Wei Wang 1 2,  Xiaoqian Ma 1 2
Affiliations

Affiliations

  • 1 Institute for Cell Transplantation and Gene Therapy, The 3rd Xiangya Hospital of Central South University, Changsha 410000, China.
  • 2 Engineering and Technology Research Center for Xenotransplantation of Human Province, Changsha 410000, China.
  • 3 Centre for Transplant and Renal Research (CTRR), Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, NSW, Australia.
PMID: 36139075 DOI: 10.3390/biom12091236
Abstract

Pancreatic beta cells are highly susceptible to oxidative stress, which plays a crucial role in diabetes outcomes. Progress has been slow to identify molecules that could be utilized to enhance cell survival and function under oxidative stress. Itaconate, a byproduct of the tricarboxylic acid cycle, has both anti-inflammatory and antioxidant properties. The effects of itaconate on beta cells under oxidative stress are relatively unknown. We explored the effects of 4-octyl itaconate-a cell-permeable derivative of itaconate-on MIN6 (a beta cell model) under oxidative stress conditions caused by hypoxia, along with its mechanism of action. Treatment with 4-OI reversed hypoxia-induced cell death, reduced ROS production, and inhibited cell death pathway activation and inflammatory cytokine secretion in MIN6 cells. The 4-OI treatment also suppressed Lactate Dehydrogenase A (LDHA)activity, which increases under hypoxia. Treatment of cells with the ROS scavenger NAC and LDHA-specific inhibitor FX-11 reproduced the beneficial effects of 4-OI on MIN6 cell viability under oxidative stress conditions, confirming its role in regulating ROS production. Conversely, overexpression of LDHA reduced the beneficial effects exerted by 4-OI on cells. Our findings provide a strong rationale for using 4-OI to prevent the death of MIN6 cells under oxidative stress.

Keywords

hypoxia; itaconate; lactate dehydrogenase A; oxidative stress; pancreatic beta cells.

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