Stoll Shaunrick, Xi Jing, Ma Ben, Leimena Christiana, Behringer Erik J, Qin Gangjian, Qiu Hongyu
*Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California 92350.
Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California 92350.
Toxicol Sci. 2019 Oct 1;171(2):473-484. doi: 10.1093/toxsci/kfz164.
Stress-induced mitochondrial calcium (Ca2+) overload is a key cellular toxic effectors and a trigger of cardiomyocyte death during cardiac ischemic injury through the opening of mitochondrial permeability transition pore (mPTP). We previously found that the valosin-containing protein (VCP), an ATPase-associated protein, protects cardiomyocytes against stress-induced death and also inhibits mPTP opening in vitro. However, the underlying molecular mechanisms are not fully understood. Here, we tested our hypothesis that VCP acts as a novel regulator of mitochondrial Ca2+ uptake proteins and resists cardiac mitochondrial Ca2+ overload by modulating mitochondrial Ca2+ homeostasis. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the heart compared to the wild type (WT) mouse, we found that, under the pathological extra-mitochondrial Ca2+ overload, Ca2+ entry into cardiac mitochondria was reduced in VCP TG mice compared to their little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca2+ challenge. Mechanistically, overexpression of VCP in the heart resulted in post-translational protein degradation of the mitochondrial Ca2+ uptake protein 1, an activator of the mitochondria Ca2+ uniporter that is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca2+ homeostasis and unlock the potential mechanism by which VCP confers its cardioprotection.
应激诱导的线粒体钙（Ca2+）超载是一种关键的细胞毒性效应因子，在心脏缺血性损伤期间，通过线粒体通透性转换孔（mPTP）的开放，它是心肌细胞死亡的触发因素。我们之前发现，含缬酪肽蛋白（VCP），一种与ATP酶相关的蛋白，可保护心肌细胞免受应激诱导的死亡，并且在体外也能抑制mPTP的开放。然而，其潜在的分子机制尚未完全明确。在此，我们验证了我们的假设，即VCP作为线粒体Ca2+摄取蛋白的新型调节因子，通过调节线粒体Ca2+稳态来抵抗心脏线粒体Ca2+超载。通过使用心脏特异性转基因（TG）小鼠模型，与野生型（WT）小鼠相比，该模型中心脏中VCP的表达量过表达了3.5倍，我们发现，在病理性细胞外线粒体Ca2+超载情况下，与匹配的WT小鼠相比，VCP TG小鼠心脏线粒体中的Ca2+内流减少，随后在Ca2+刺激下可防止mPTP开放和ATP耗竭。从机制上讲，心脏中VCP的过表达导致线粒体Ca2+摄取蛋白1的翻译后蛋白降解，该蛋白是线粒体Ca2+单向转运体的激活剂，负责线粒体钙摄取。总之，我们的结果揭示了VCP在心脏线粒体Ca2+稳态中的新调节作用，并揭示了VCP发挥心脏保护作用的潜在机制。
