Liu Julia C, Liu Jie, Holmström Kira M, Menazza Sara, Parks Randi J, Fergusson Maria M, Yu Zu-Xi, Springer Danielle A, Halsey Charles, Liu Chengyu, Murphy Elizabeth, Finkel Toren
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Cell Rep. 2016 Aug 9;16(6):1561-1573. doi: 10.1016/j.celrep.2016.07.011. Epub 2016 Jul 28.
MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1(-/-) mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1(-/-) mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP. Older MICU1(-/-) mice show marked, spontaneous improvement coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression. Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1(-/-) mice. Together, these results demonstrate that MICU1 serves as a molecular gatekeeper preventing calcium overload and suggests that modulating the calcium uniporter could have widespread therapeutic benefits.
MICU1是线粒体钙单向转运体的一个组成部分，线粒体钙单向转运体是一种多蛋白复合物，还包括MICU2、MCU和EMRE。在此，我们描述了一种MICU1缺陷的小鼠模型。MICU1基因敲除小鼠的线粒体表现出钙摄取改变，MICU1基因敲除导致围产期死亡率显著升高，但并非完全死亡。与患病患者相似，存活的MICU1基因敲除小鼠表现出明显的共济失调和肌肉无力。在生命早期，这些动物表现出一系列生化异常，包括静息线粒体钙水平升高、线粒体形态改变和ATP减少。年龄较大的MICU1基因敲除小鼠表现出明显的自发改善，同时线粒体钙处理能力提高，EMRE表达随年龄增长而降低。值得注意的是，敲除EMRE的一个等位基因有助于使钙摄取正常化，同时挽救年轻MICU1基因敲除小鼠中观察到的高围产期死亡率。总之，这些结果表明MICU1作为分子守门人可防止钙超载，并表明调节钙单向转运体可能具有广泛的治疗益处。
