Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Poster Abstracts

34-POS Board 19 MECHANISM OF DUAL MODULATORY EFFECTS OF SPERMINE ON THE MITOCHONDRIAL CALCIUM UNIPORTER COMPLEX Yung-Chi Tu 1 ; Ming-Feng Tsai 1 ; 1 University of Virginia, Molecular Physiology and Biological Physics, Charlottesville, VA, USA The mitochondria calcium uniporter is a multi-subunit calcium channel complex, which mediates mitochondrial calcium uptake. It is crucial for regulating mitochondria metabolism and intracellular calcium signaling. The uniporter is composed of the pore-forming subunit MCU, an EMRE subunit, and the regulatory subunits MICU1 and MICU2, which can form a MICU1-2 heterodimer. We have shown before that MICU1-2 regulates the uniporter by occluding the MCU pore under resting cellular [Ca 2+ ]. When [Ca 2+ ] increases, MICU1-2 would separate from MCU to open the uniporter. For decades, it has been known that spermine, a polyamine ubiquitously present in animal cells, can potentiate the uniporter, but the underlying molecular mechanism remains unclear. Here, we demonstrate that spermine exhibits dual modulatory effects on the uniporter. Under physiological concentrations of spermine, it enhances the uniporter’s activity by attaching to the bilayer surface and disrupting MICU1-2 block of MCU, allowing the uniporter to take up more Ca 2+ in low Ca 2+ conditions. This potentiation effect does not require MICU2 or the EF-hand Ca 2+ -binding motif in MICU1. Lastly, we show that when spermine concentration rises to millimolar levels, it can inhibit the uniporter by blocking the pore in a MICU1-independent manner. Together, our findings solved the decade-old puzzle about how spermine regulates the mitochondria calcium uptake process. Furthermore, our work nicely explains why cardiac mitochondria show no response to spermine — the uniporter in cardiac mitochondria is MICU1-derugalated.

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