Tu Yung-Chi, Lee I-Chi, Chang Tsai-Wei, Lee Vivian, Chao Fan-Yi, Geltser Eitel R, Tsai Ming-Feng
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
J Biol Chem. 2025 Mar;301(3):108218. doi: 10.1016/j.jbc.2025.108218. Epub 2025 Jan 23.
The mitochondrial Ca uniporter is the Ca channel responsible for mitochondrial Ca uptake. It plays crucial physiological roles in regulating oxidative phosphorylation, intracellular Ca signaling, and cell death. The uniporter contains the pore-forming MCU subunit, the auxiliary EMRE protein, and the regulatory MICU1 subunit, which blocks the MCU pore under resting cellular Ca concentrations. It has been known for decades that spermine, a biological polyamine ubiquitously present in animal cells, can enhance mitochondrial Ca uptake, but the underlying mechanisms remain incompletely understood. In this study, we demonstrate that spermine exerts both potentiation and inhibitory effects on the uniporter. At physiological concentrations, spermine binds to membranes and disrupts MCU-MICU1 interactions, thereby opening the uniporter to import more Ca. However, at millimolar concentrations, spermine also inhibits the uniporter by targeting the pore-forming region in a MICU1-independent manner. These findings provide molecular insights into how cells can use spermine to control the critical processes of mitochondrial Ca signaling and homeostasis.
线粒体钙单向转运体是负责线粒体摄取钙的钙通道。它在调节氧化磷酸化、细胞内钙信号传导和细胞死亡中发挥着关键的生理作用。该单向转运体包含形成孔道的MCU亚基、辅助性EMRE蛋白以及调节性MICU1亚基，在静息细胞钙浓度下，MICU1亚基会阻断MCU孔道。几十年来人们一直知道，精胺这种在动物细胞中普遍存在的生物多胺能够增强线粒体对钙的摄取，但其潜在机制仍未完全明确。在本研究中，我们证明精胺对该单向转运体既有增强作用又有抑制作用。在生理浓度下，精胺与膜结合并破坏MCU-MICU1的相互作用，从而打开单向转运体以摄取更多的钙。然而，在毫摩尔浓度下，精胺还会以不依赖MICU1的方式靶向孔道形成区域来抑制单向转运体。这些发现为细胞如何利用精胺来控制线粒体钙信号传导和体内平衡的关键过程提供了分子层面的见解。
