衣霉素诱导的内质网应激损伤心脏线粒体中的复合物I。
Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria.
作者信息
Chen Qun, Thompson Jeremy, Hu Ying, Lesnefsky Edward J
机构信息
Division of Cardiology, Department of Medicine, Pauley Heart Center, Richmond, VA 23298, USA.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
出版信息
Life (Basel). 2022 Aug 9;12(8):1209. doi: 10.3390/life12081209.
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 Ca-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.
背景
使用毒胡萝卜素诱导急性内质网（ER）应激会导致小鼠心脏复合体I损伤。毒胡萝卜素通过抑制内质网中的钙 - ATP酶增加线粒体钙含量，从而损害复合体I。衣霉素（TUNI）用于通过抑制蛋白质折叠来诱导内质网应激。我们探究了衣霉素诱导的内质网应激是否会导致复合体I损伤。
方法
使用衣霉素（0.4mg/kg）诱导C57BL/6小鼠的内质网应激。在衣霉素处理24或72小时后分离心脏线粒体，用于线粒体功能分析。
结果
仅在衣霉素处理72小时后的小鼠中内质网应激增加。与载体相比，衣霉素处理降低了复合体I底物的氧化磷酸化，同时复合体I活性降低。衣霉素处理的小鼠中包括NBUPL和NDUFS7在内的复合体I亚基含量降低。衣霉素处理激活了胞质和线粒体钙蛋白酶1。我们的结果表明，衣霉素诱导的内质网应激通过降解包括NDUFS7在内的亚基来损害复合体I。
结论
使用衣霉素诱导内质网应激通过激活钙蛋白酶1导致复合体I损伤。
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