Regulation and function of mitochondrial calcium uniporter in the heart

总结 心力衰竭是导致死亡的主要原因，也是美国医疗保健的巨大负担。最近， 能量代谢受损已成为心脏泵血功能衰竭的关键因素， 据报道，在代谢研究和线粒体生物学方面取得了新的突破。的一个关键 在跳动的心脏中调节线粒体功能的机制是通过线粒体的钙摄取 钙单向转运体（MCU）。令人惊讶的是，MCU基因敲除小鼠表现出正常的表型、心脏性能和 线粒体功能，表明MCU在正常心脏中是不稳定的。MCU的病理意义 或线粒体钙在肥大和衰竭的心脏中的作用也是难以捉摸和高度争论的。最后， MCU基因表达在心脏中的调节尚未探索。这些知识差距削弱了 最初的兴奋点燃了发现的分子身份的MCU。我们的初步结果很有希望 表明MCU表达在围产期心脏和慢性应激成人心脏中通过转录调控高表达， 通过钙-钙调蛋白依赖性蛋白激酶II δB（CaMK II δB）调节。功能丧失和功能恢复 功能途径揭示MCU通过以下途径在心脏肥大和功能障碍中起代偿作用： 调节胞质钙和细胞死亡途径。没想到，围产期敲除MCU 加重压力超负荷诱导的成年小鼠心脏功能障碍。基于这些结果，我们假设 MCU表达在围产期心脏和应激的成人心脏中策略性地增强， 病理性心脏重塑我们将在三个具体目标中检验这一假设。康贝特人将以 CaMKIIδB调控MCU基因表达的分子机制。我们将回答为什么心脏 肥大和功能障碍通过MCU上调而缓解，但通过MCU抑制而加剧。此外，委员会认为， 我们将探讨MCU在围产期心脏中的调节作用以及MCU如何限制压力超负荷引起的心脏收缩和舒张功能。 成人心脏功能障碍这项研究的结果将描绘一个完整的机制，MCU基因表达 在心脏中得到很好的调节。本研究还旨在揭示MCU在围产期心脏中的新作用， 肥大成人心脏对抗由多种应激诱导的心脏重塑。

Summary Heart failure is the leading cause of death and a huge burden on health care in the United States. Recently, impaired energy metabolism has emerged as a key contributor to the failure of the heart’s pumping function, and new breakthroughs in metabolic research and mitochondrial biology have been reported. One of the key mechanisms for regulating mitochondrial function in the beating heart is calcium uptake through mitochondrial calcium uniporter (MCU). Surprisingly, MCU knockout mice exhibited normal phenotype, heart performance and mitochondrial function, indicating that MCU is dispensable in the normal heart. Pathological significance of MCU or mitochondrial calcium in the hypertrophic and failing heart is also elusive and highly debated. Finally, how MCU gene expression is regulated in the heart remains unexplored. These gaps in knowledge diminished the initial excitement ignited by the discovery of the molecular identity of MCU. Our promising preliminary results show that MCU expression is high in perinatal heart and in the chronically stressed adult heart via transcriptional regulation by calcium-calmodulin dependent protein kinase II δB (CaMKIIδB). Loss-of-function and gain-of- function approaches reveal that MCU plays a compensatory role in heart hypertrophy and dysfunction through modulating cytosolic calcium and cell death pathways. Unexpectedly, knockout MCU during the perinatal stage worsened pressure overload-induced heart dysfunction in adult mice. Based on these results, we hypothesize that MCU expression is strategically enhanced in the perinatal heart and in the stressed adult heart to ameliorate pathological heart remodeling. We will test this hypothesis in three Specific Aims. We will determine the molecular mechanisms by which CaMKIIδB regulates MCU gene expression. We will answer why cardiac hypertrophy and dysfunction are alleviated by MCU upregulation but aggravated by MCU inhibition. Furthermore, we will investigate the regulation of MCU in perinatal heart and how MCU limits pressure overload-induced dysfunction in the adult heart. Results of this study will depict a full mechanism by which MCU gene expression is fine tuned in the heart. This study also aims to uncover novel roles of MCU in perinatal heart and in the hypertrophic adult heart that counteract cardiac remodeling induced by multiple stresses.