SR-Mitochondria Crosstalk Shapes Ca Signalling to Impact Pathophenotype in Disease Models Marked by Dysregulated Intracellular Ca Release.
SR-Mitochondria Crosstalk Shapes Ca Signalling to Impact Pathophenotype in Disease Models Marked by Dysregulated Intracellular Ca Release.
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DOI：
10.1093/cvr/cvab324
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发表时间：
2022-10-21
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
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肌浆网钙释放通道RyR 2的舒张期钙释放（DCR）与多种心脏病理有关，但其在不同心脏病理形成中的确切作用尚不清楚。我们假设SR-线粒体相互作用通过塑造Ca信号传导而促成疾病表型。在这项研究中，采用了一种由DCR标记的儿茶酚胺能多态性室性心动过速的遗传模型（CASQ 2敲除的CPVT 2模型）和一种果糖喂养的小鼠（FFD）的糖尿病前期心肌病模型。线粒体Ca（mCa）分别通过靶向线粒体Ca单向转运体（MCU）或渗透性转换孔（mPTP）、mCa摄取和排出机制的ATP酶调节。MCU激活剂消除了CPVT 2的Ca波，但加重了FFD细胞的Ca波。从机制上讲，这归因于线粒体分别作为Ca缓冲剂或活性氧物质（mtROS）来源的功能，以加剧RyR 2的功能。增强mCa摄取分别降低和升高CPVT 2和FFD中的mtROS产生。在CPVT 2中，与FFD相比，线粒体在透化细胞中摄取更多的Ca，并且在完整细胞中具有更高水平的mCa含量。在CPVT 2模型中，MCU的条件性消融导致致死性和心脏重塑，但在FFD模型中减少了心律失常。与此同时，CPVT 2线粒体还采用上调的mPTP介导的Ca流出来避免mCa过载，如MitoWinks（mPTP介导的Ca流出的指标）与FFD相比发生率升高所示。药理学和遗传抑制mPTP促进线粒体ROS的生产和加剧CPVT 2的心肌细胞钙处理。此外，mPTP的遗传抑制加剧了CPVT 2的心律失常。与FFD相比，FFD更容易受到mtROS依赖性RyR 2泄漏的影响，在CPVT 2线粒体缓冲液中SR衍生的DCR可减轻Ca依赖性病理性重塑，并依赖mPTP介导的Ca流出来避免mCa过载。SR-线粒体相互作用通过连续地形成细胞内Ca信号传导而导致不同的病理学。
Diastolic Ca release (DCR) from sarcoplasmic reticulum (SR) Ca release channel ryanodine receptor (RyR2) has been linked to multiple cardiac pathologies, but its exact role in shaping divergent cardiac pathologies remains unclear. We hypothesize that the SR-mitochondria interplay contributes to disease phenotypes by shaping Ca signalling. A genetic model of catecholaminergic polymorphic ventricular tachycardia (CPVT2 model of CASQ2 knockout) and a pre-diabetic cardiomyopathy model of fructose-fed mice (FFD), both marked by DCR, are employed in this study. Mitochondria Ca (mCa) is modulated by pharmacologically targeting mitochondria Ca uniporter (MCU) or permeability transition pore (mPTP), mCa uptake, and extrusion mechanisms, respectively. An MCU activator abolished Ca waves in CPVT2 but exacerbated waves in FFD cells. Mechanistically this is ascribed to mitochondria’s function as a Ca buffer or source of reactive oxygen species (mtROS) to exacerbate RyR2 functionality, respectively. Enhancing mCa uptake reduced and elevated mtROS production in CPVT2 and FFD, respectively. In CPVT2, mitochondria took up more Ca in permeabilized cells, and had higher level of mCa content in intact cells vs. FFD. Conditional ablation of MCU in the CPVT2 model caused lethality and cardiac remodelling, but reduced arrhythmias in the FFD model. In parallel, CPVT2 mitochondria also employ up-regulated mPTP-mediated Ca efflux to avoid mCa overload, as seen by elevated incidence of MitoWinks (an indicator of mPTP-mediated Ca efflux) vs. FFD. Both pharmacological and genetic inhibition of mPTP promoted mtROS production and exacerbation of myocyte Ca handling in CPVT2. Further, genetic inhibition of mPTP exacerbated arrhythmias in CPVT2. In contrast to FFD, which is more susceptible to mtROS-dependent RyR2 leak, in CPVT2 mitochondria buffer SR-derived DCR to mitigate Ca-dependent pathological remodelling and rely on mPTP-mediated Ca efflux to avoid mCa overload. SR-mitochondria interplay contributes to the divergent pathologies by disparately shaping intracellular Ca signalling.
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影响因子：
6.2
作者：
Halloran, PF;Helms, LMH;Noujaim, J
通讯作者：
Noujaim, J
内膜的四十千克蛋白是线粒体钙Uniporter。
影响因子：
64.8
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario
影响因子：
64.8
作者：
Baines, CP;Kaiser, RA;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
4.8
作者：
Korge, Paavo;Yang, Ling;Weiss, James N.
通讯作者：
Weiss, James N.
影响因子：
64.8
作者：
Baughman, Joshua M.;Perocchi, Fabiana;Girgis, Hany S.;Plovanich, Molly;Belcher-Timme, Casey A.;Sancak, Yasemin;Bao, X. Robert;Strittmatter, Laura;Goldberger, Olga;Bogorad, Roman L.;Koteliansky, Victor;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.