Deb Arpita, Tow Brian D, Hao Jie, Nguyen Branden L, Gomez Valeria, Stewart James A, Smuder Ashley J, Knollmann Bjorn C, Wang Ying, Liu Bin
Department of Biological Sciences, Mississippi State University, Starkville, MS 39762, USA.
Plant Pathology Department, University of Florida, Gainesville, FL 32611, USA.
J Mol Cell Cardiol Plus. 2024 Dec;10. doi: 10.1016/j.jmccpl.2024.100093. Epub 2024 Sep 10.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca to protect the heart from cardiac remodeling.
The Mitochondrial Ca uniporter (MCU), the main mitochondrial Ca uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2-MCU model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2-MCU hearts. Live-cell imaging identified altered Ca handling and increased oxidative stress in CASQ2-MCU myocytes. The activation status of Ca-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2-MCU model. RNAseq identified changes in the transcriptome of the CASQ2-MCU hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression.
We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca uptake is crucial for preventing pathological cardiac remodeling in CPVT.
儿茶酚胺能多形性室性心动过速（CPVT）是一种遗传性心律失常综合征，由钙（Ca）释放通道兰尼碱受体（RyR2）及其辅助蛋白的突变引起。这些突变使通道出现渗漏，导致钙依赖性心律失常。除心律失常外，CPVT心脏通常缺乏结构性心脏重塑，这一特征在其他以RyR2渗漏为标志的心脏疾病（心力衰竭、糖尿病前期）中也经常观察到。最近的研究表明，线粒体能够容纳更多的钙内流以抑制CPVT中的心律失常。因此，我们假设CPVT线粒体可以吸收舒张期钙以保护心脏免受心脏重塑的影响。
在2型钙结合蛋白（CASQ2）基因敲除的CPVT模型中，有条件地敲除主要的线粒体钙摄取蛋白——线粒体钙单向转运体（MCU）。通过超声心动图评估，CASQ2-MCU模型的体内心脏功能受损。在CASQ2-MCU心脏中也观察到心脏扩张和细胞肥大。活细胞成像显示CASQ2-MCU心肌细胞中钙处理改变且氧化应激增加。在CASQ2-MCU模型中，钙依赖性重塑途径（CaMKII、钙调神经磷酸酶）的激活状态未改变。RNA测序确定了CASQ2-MCU心脏转录组的变化，这与胎儿基因重新表达的经典心脏重塑程序不同。
我们提供了遗传学证据，证明线粒体在CPVT中起保护作用。MCU依赖性钙摄取对于预防CPVT中的病理性心脏重塑至关重要。
