Tu Yung-Chi, Chao Fan-Yi, Tsai Ming-Feng
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
bioRxiv. 2023 Jun 6:2023.06.06.543936. doi: 10.1101/2023.06.06.543936.
The mitochondrial uniporter mediates the crucial cellular process of mitochondrial uptake, which regulates cell bioenergetics, intracellular signaling, and cell death initiation. The uniporter contains the pore-forming MCU subunit, an EMRE protein that binds to MCU, and the regulatory MICU1 subunit, which can dimerize with MICU1 or MICU2 and under resting cellular [] occludes the MCU pore. It has been known for decades that spermine, which is ubiquitously present in animal cells, can enhance mitochondrial uptake, but the underlying mechanisms remain unclear. Here, we show that spermine exerts dual modulatory effects on the uniporter. In physiological concentrations of spermine, it enhances uniporter activity by breaking the physical interactions between MCU and the MICU1-containing dimers to allow the uniporter to constitutively take up even in low [] conditions. This potentiation effect does not require MICU2 or the EF-hand motifs in MICU1. When [spermine] rises to millimolar levels, it inhibits the uniporter by targeting the pore region in a MICU-independent manner. The MICU1-dependent spermine potentiation mechanism proposed here, along with our previous finding that cardiac mitochondria have very low MICU1, can explain the puzzling observation in the literature that mitochondria in the heart show no response to spermine.
线粒体单向转运体介导线粒体摄取这一关键的细胞过程，该过程调节细胞生物能量学、细胞内信号传导以及细胞死亡起始。单向转运体包含形成孔道的MCU亚基、与MCU结合的EMRE蛋白以及调节性MICU1亚基，MICU1可与MICU1或MICU2二聚化，在静息细胞状态下会封闭MCU孔道。几十年来人们已知，动物细胞中普遍存在的精胺可增强线粒体摄取，但潜在机制仍不清楚。在此，我们表明精胺对单向转运体具有双重调节作用。在生理浓度的精胺条件下，它通过打破MCU与含MICU1二聚体之间的物理相互作用来增强单向转运体活性，使单向转运体即使在低[具体条件未给出]条件下也能持续摄取。这种增强作用不需要MICU2或MICU1中的EF手基序。当[精胺]升至毫摩尔水平时，它以不依赖MICU的方式靶向孔道区域来抑制单向转运体。这里提出的依赖MICU1的精胺增强机制，连同我们之前发现心脏线粒体中MICU1含量非常低，能够解释文献中令人困惑的观察结果，即心脏中的线粒体对精胺无反应。
