Hyperglycemia Induces Endoplasmic Reticulum Stress in Atrial Cardiomyocytes, and Mitofusin-2 Downregulation Prevents Mitochondrial Dysfunction and Subsequent Cell Death.

Abstract

Mitochondrial oxidative stress and dysfunction play an important role of atrial remodeling and atrial fibrillation (AF) in diabetes mellitus. Endoplasmic reticulum (ER) stress has been linked to both physiological and pathological states including diabetes. The aim of this project is to explore the roles of ER stress in hyperglycemia-induced mitochondrial dysfunction and cell death of atrial cardiomyocytes. High glucose upregulated ER stress, mitochondrial oxidative stress, and mitochondria-associated ER membrane (MAM)- enriched proteins (such as glucose-regulated protein 75 (GRP75) and mitofusin-2 (Mfn2)) of primary cardiomyocytes in vitro. Sodium phenylbutyrate (4-PBA) prevented the above changes. Silencing of Mfn2 in HL-1 cells decreased the Ca2+ transfer from ER to mitochondria under ER stress conditions, which were induced by the ER stress agonist, tunicamycin (TM). Electron microscopy data suggested that Mfn2 siRNA significantly disrupted ER-mitochondria tethering in ER stress-injured HL-1 cells. Mfn2 silencing attenuated mitochondrial oxidative stress and Ca2+ overload, increased mitochondrial membrane potential and mitochondrial oxygen consumption, and protected cells from TM-induced apoptosis. In summary, Mfn2 plays an important role in high glucose-induced ER stress in atrial cardiomyocytes, and Mfn2 silencing prevents mitochondrial Ca2+ overload-mediated mitochondrial dysfunction, thereby decreasing ER stress-mediated cardiomyocyte cell death.

• Authors: Ming Yuan, Mengqi Gong, Zhiwei Zhang, Lei Meng, Gary Tse, Yungang Zhao, Qiankun Bao, Yue Zhang, Meng Yuan, Xing Liu, Guangping Li, Tong Liu
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2020 Pg. 6569728 ( 2020) ISSN: 1942-0994 [Electronic] United States
• PMID: 33149811 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Ming Yuan et al.

Chemical References

• Biomarkers
• Mitochondrial Proteins
• RNA, Small Interfering
• Reactive Oxygen Species
• Tunicamycin
• GTP Phosphohydrolases
• Mfn2 protein, rat
• Glucose
• Calcium

Topics

• Animals
• Apoptosis (drug effects, genetics)
• Biomarkers (metabolism)
• Calcium (metabolism)
• Cell Death (drug effects)
• Cell Line
• Down-Regulation (drug effects)
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• GTP Phosphohydrolases (genetics, metabolism)
• Gene Silencing
• Glucose (toxicity)
• Heart Atria (pathology)
• Hyperglycemia (pathology)
• Intracellular Membranes (drug effects, metabolism)
• Mitochondria, Heart (metabolism, ultrastructure)
• Mitochondrial Proteins (genetics, metabolism)
• Models, Biological
• Myocytes, Cardiac (metabolism, pathology, ultrastructure)
• Oxidative Stress (drug effects)
• RNA, Small Interfering (metabolism)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Tunicamycin (pharmacology)
• Up-Regulation (drug effects)