Methylglyoxal induces cell death through endoplasmic reticulum stress-associated ROS production and mitochondrial dysfunction.
Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are two important leading causes of acquired blindness in developed countries. As accumulation of advanced glycation end products (AGEs) in retinal pigment epithelial (RPE) cells plays an important role in both DR and AMD, and the methylglyoxal (MGO) within the AGEs exerts irreversible effects on protein structure and function, it is crucial to understand the underlying mechanism of MGO-induced RPE cell death. Using ARPE-19 as the cell model, this study revealed that MGO induces RPE cell death through a caspase-independent manner, which relying on reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, intracellular calcium elevation and endoplasmic reticulum (ER) stress response. Suppression of ROS generation can reverse the MGO-induced ROS production, MMP loss, intracellular calcium increase and cell death. Moreover, store-operated calcium channel inhibitors MRS1845 and YM-58483, but not the inositol 1,4,5-trisphosphate (IP3) receptor inhibitor xestospongin C, can block MGO-induced ROS production, MMP loss and sustained intracellular calcium increase in ARPE-19 cells. Lastly, inhibition of ER stress by salubrinal and 4-PBA can reduce the MGO-induced intracellular events and cell death. Therefore, our data indicate that MGO can decrease RPE cell viability, resulting from the ER stress-dependent intracellular ROS production, MMP loss and increased intracellular calcium increase. As MGO is one of the components of drusen in AMD and is the AGEs adduct in DR, this study could provide a valuable insight into the molecular pathogenesis and therapeutic intervention of AMD and DR.
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City, Taiwan.|School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
Chi-Ming
CM
Chan
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Duen-Yi
DY
Huang
Medical Research Center, Cardinal Tien Hospital, New Taipei City, Taiwan.
Yi-Pin
YP
Huang
Medical Research Center, Cardinal Tien Hospital, New Taipei City, Taiwan.
Shu-Hao
SH
Hsu
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Lan-Ya
LY
Kang
Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan.
Chung-Min
CM
Shen
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Wan-Wan
WW
Lin
D000328:Adult; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D011765:Pyruvaldehyde / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D015220:Calcium Channels; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D011765:Pyruvaldehyde; D020169:Caspases; D002118:Calcium
ER stress; intracellular calcium; methylglyoxal; mitochondria; reactive oxygen species; retinal pigment epithelium