Department of Neuroscience and Pharmacology and Iowa Neuroscience Institute, University of Iowa College of Medicine, Iowa City, IA, 52242, USA.
Department of Molecular Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, IA, 52242, USA.
Cell Calcium. 2021 Jun;96:102382. doi: 10.1016/j.ceca.2021.102382. Epub 2021 Feb 22.
Mitochondrial Ca transport is essential for regulating cell bioenergetics, Ca signaling and cell death. Mitochondria accumulate Ca via the mitochondrial Ca uniporter (MCU), whereas Ca is extruded by the mitochondrial Na/Ca (mtNCX) and H/Ca exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca overload. Recent work demonstrated that MCU activity varies significantly among tissues, likely reflecting tissue-specific Ca signaling and energy needs. It is less clear whether this diversity in MCU activity is matched by tissue-specific diversity in mitochondrial Ca extrusion. Here we compared properties of mitochondrial Ca extrusion in three tissues with prominent mitochondria function: brain, heart and liver. At the transcript level, expression of the Na/Ca/Li exchanger (NCLX), which has been proposed to mediate mtNCX transport, was significantly greater in liver than in brain or heart. At the functional level, Na robustly activated Ca efflux from brain and heart mitochondria, but not from liver mitochondria. The mtNCX inhibitor CGP37157 blocked Ca efflux from brain and heart mitochondria but had no effect in liver mitochondria. Replacement of Na with Li to test the involvement of NCLX, resulted in a slowing of mitochondrial Ca efflux by ∼70 %. Collectively, our findings suggest that mtNCX is responsible for Ca extrusion from the mitochondria of the brain and heart, but plays only a small, if any, role in mitochondria of the liver. They also reveal that Li is significantly less effective than Na in driving mitochondrial Ca efflux.
线粒体 Ca 转运对于调节细胞生物能量学、Ca 信号和细胞死亡至关重要。线粒体通过线粒体 Ca 单向转运体（MCU）积累 Ca，而 Ca 则通过线粒体 Na/Ca（mtNCX）和 H/Ca 交换器排出。这些过程之间的平衡对于防止有毒的线粒体 Ca 过载至关重要。最近的工作表明，MCU 活性在不同组织之间存在显著差异，这可能反映了组织特异性的 Ca 信号和能量需求。但 MCU 活性的这种多样性是否与线粒体 Ca 外排的组织特异性多样性相匹配还不太清楚。在这里，我们比较了三种具有显著线粒体功能的组织（脑、心脏和肝脏）中线粒体 Ca 外排的特性。在转录水平上，Na/Ca/Li 交换体（NCLX）的表达，其被提出介导 mtNCX 转运，在肝脏中的表达明显高于脑或心脏。在功能水平上，Na 强烈激活脑和心脏线粒体的 Ca 外排，但不激活肝脏线粒体。mtNCX 抑制剂 CGP37157 阻断脑和心脏线粒体的 Ca 外排，但对肝脏线粒体没有影响。用 Li 替代 Na 来测试 NCLX 的参与，导致线粒体 Ca 外排的速度减慢了约 70%。总的来说，我们的研究结果表明，mtNCX 负责脑和心脏线粒体的 Ca 外排，但在肝脏线粒体中只起很小的作用，如果有的话。它们还表明 Li 在驱动线粒体 Ca 外排方面的效果明显不如 Na。
