Distinct effects of cardiac mitochondrial calcium uniporter inactivation via EMRE deletion in the short and long term.
Distinct effects of cardiac mitochondrial calcium uniporter inactivation via EMRE deletion in the short and long term.
复制标题
通过 EMRE 缺失导致心脏线粒体钙单向转运蛋白失活的短期和长期的独特影响。
DOI：
10.1016/j.yjmcc.2023.05.007
复制
发表时间：
2023
影响因子：
5
通讯作者：
Liu,JuliaC
中科院分区：
文献类型：
--
作者：
ChapoyVillanueva,Hector;Sung,JaeHwi;Stevens,JackieA;Zhang,MichaelJ;Nelson,PeytonM;Denduluri,LalithaS;Feng,Feng;O'Connell,TimothyD;Townsend,DeWayne;Liu,JuliaC
将 Ca2+ 转运至线粒体被认为可以刺激 ATP 的产生，这是心脏战斗或逃跑反应的关键过程，但过量的 Ca2+ 会引发细胞死亡。线粒体Ca2+单向转运蛋白复合物是Ca2+转运至线粒体的主要途径，其中通道形成蛋白MCU和调节蛋白EMRE对于活性至关重要。在之前的研究中，慢性McuorEmredeletion与急性心脏Mcuordeletion在对肾上腺素能刺激和缺血/再灌注（I/R）损伤的反应方面有所不同，尽管线粒体快速Ca2+摄取具有同等的失活作用。为了探索单向转运蛋白活性的慢性和急性丧失之间的差异，我们使用新型条件心脏特异性、他莫昔芬诱导的小鼠模型比较了短期和长期的 Emredeletion。成年小鼠短期 Emredeletion（他莫昔芬后 3 周）后，心脏线粒体无法吸收 Ca2+，基础线粒体 Ca2+ 水平较低，并且 Ca2+ 诱导的 ATP 产生和 mPTP 开放减弱。此外，短期 EMRE 损失会减弱心脏对肾上腺素能刺激的反应，并改善体外 I/R 模型中心脏功能的维持。然后，我们测试了成年期长期缺乏 EMRE（服用他莫昔芬 3 个月）是否会导致不同的结果。长期Emre删除后，线粒体Ca2+处理和功能，以及心脏对肾上腺素能刺激的反应，与短期删除时类似地受到损害。然而有趣的是，从长远来看，对缺血再灌注损伤的保护作用消失了。这些数据表明，没有单向转运蛋白功能的几个月不足以恢复生物能反应，但足以恢复对 I/R 的易感性。
Transport of Ca2+into mitochondria is thought to stimulate the production of ATP, a critical process in the heart's fight or flight response, but excess Ca2+can trigger cell death. The mitochondrial Ca2+uniporter complex is the primary route of Ca2+transport into mitochondria, in which the channel-forming protein MCU and the regulatory protein EMRE are essential for activity. In previous studies, chronicMcuorEmredeletion differed from acute cardiacMcudeletion in response to adrenergic stimulation and ischemia/reperfusion (I/R) injury, despite equivalent inactivation of rapid mitochondrial Ca2+uptake. To explore this discrepancy between chronic and acute loss of uniporter activity, we compared short-term and long-termEmredeletion using a novel conditional cardiac-specific, tamoxifen-inducible mouse model. After short-termEmredeletion (3 weeks post-tamoxifen) in adult mice, cardiac mitochondria were unable to take up Ca2+, had lower basal mitochondrial Ca2+levels, and displayed attenuated Ca2+-induced ATP production and mPTP opening. Moreover, short-term EMRE loss blunted cardiac response to adrenergic stimulation and improved maintenance of cardiac function in anex vivoI/R model. We then tested whether the long-term absence of EMRE (3 months post-tamoxifen) in adulthood would lead to distinct outcomes. After long-termEmredeletion, mitochondrial Ca2+handling and function, as well as cardiac response to adrenergic stimulation, were similarly impaired as in short-term deletion. Interestingly, however, protection from I/R injury was lost in the long-term. These data suggest that several months without uniporter function are insufficient to restore bioenergetic response but are sufficient to restore susceptibility to I/R.