Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Abstract

Background: Induction of acute ER (endoplasmic reticulum) stress using thapsigargin contributes to complex I damage in mouse hearts. Thapsigargin impairs complex I by increasing mitochondrial calcium through inhibition of Ca2+-ATPase in the ER. Tunicamycin (TUNI) is used to induce ER stress by inhibiting protein folding. We asked if TUNI-induced ER stress led to complex I damage. Methods: TUNI (0.4 mg/kg) was used to induce ER stress in C57BL/6 mice. Cardiac mitochondria were isolated after 24 or 72 h following TUNI treatment for mitochondrial functional analysis. Results: ER stress was only increased in mice following 72 h of TUNI treatment. TUNI treatment decreased oxidative phosphorylation with complex I substrates compared to vehicle with a decrease in complex I activity. The contents of complex I subunits including NBUPL and NDUFS7 were decreased in TUNI-treated mice. TUNI treatment activated both cytosolic and mitochondrial calpain 1. Our results indicate that TUNI-induced ER stress damages complex I through degradation of its subunits including NDUFS7. Conclusion: Induction of the ER stress using TUNI contributes to complex I damage by activating calpain 1.

Acute endoplasmic reticulum stress‐induced mitochondria respiratory chain damage: The role of activated calpains

“…The induction of acute ER stress damages the ETC in C57BL/6 mice. 1,9,19 In the present study, we find that TUNI-induced ER stress damages the ETC in tamoxifentreated CPNS1 PZ/PZ control mice but not in CPNS1 cardiacspecific deletion mice. TUNI treatment activates both cCPN1/2 and mCPN1/2 in control mice.…”

“…Our previous study showed that 72 h after a one-time TUNI treatment that ER stress was increased accompanied by mitochondrial dysfunction and damage to the ETC in C57BL/6 mice. 9 Therefore, TUNI was used in the current study to induce ER stress in control and CPNS1 T A B L E 5 ER stress induced by tunicamycin (TUNI) treatment led to an increase in select mitochondrial protein contents in control but not in deletion mice. deletion mice to test the hypothesis that CPN1/2 was a critical effector of ER stress-mediated mitochondrial dysfunction.…”

“…Our previous study showed that 72 h following TUNI treatment, the ER stress was increased in C57BL/6 mice. 9 Thus, ER stress was assessed in control and CPNS1 deletion mice at this time point. An increase in the contents of Bip 10 and eif-2α 11 were used as indicators of ER stress.…”

“…9,10 Thus, ER stress has a direct impact on mitochondrial function. 9 The induction of acute ER stress impairs the function of the mitochondrial electron transport chain (ETC) in multiple animal models. 2,11,12 The impairment of the ETC not only decreases ATP production but also promotes tissue injury via the production and release of toxic substances, including reactive oxygen species (ROS) and mitochondrial peptides.…”

Tunicamycin induced inhibition of calpain 1 and 2 enzyme activity in ovarian cancer cells

“…9 A recent in vivo study found that TN treatment activates both cytosolic and mitochondrial calpain 1 (CAPN-1). 16 In a study investigating the antitumor effect of TN, it was also found that TN inhibits cell proliferation and migration in hepatocellular carcinoma. 17 In our study, we examined the effect of TN…”