Background: A pore-forming subunit of mitochondrial Ca 2+ (mtCa 2+ ) uniporter complex (mtCUC) is encoded by MCU gene, originally known as CCDC109A. MCU function is known as a major mtCa 2+ influx pathway at the inner mitochondrial membrane in all cell types. Human MCU gene produces the canonical full-length transcript (renamed MCU-L) and a shorter transcript (termed MCU-S) that lacks the mitochondria-targeting sequence. Notably, MCU-S mRNA is highly expressed in human platelets. However, the functional significance of MCU-S in human platelets has not been fully investigated. Hypothesis: MCU-S can form Ca 2+ -permeable channels outside of mitochondria, such as the plasma membrane (PM) in the platelets. Methods: Human platelets from healthy adult donors and human megakaryoblastic leukemia cell line (MEG-01) were used for biomechanical and cell biological assays. Ca 2+ permeability via MCU-S was assessed by Ca 2+ imaging under the confocal microscope. Results: Using cell-surface protein biotinylation, we found that the plasma membrane from human platelets contains MCU and several other components of mtCUC. Platelets exhibited Ru360-sensitive Ca 2+ permeabilization via PM after switching the extracellular Ca 2+ concentration from 0 to 2 mM, even under the inhibition of the store-operated Ca 2+ entry. MEG-01 cells overexpressing MCU-S (but not the cells expressing GFP as a control or dominant-negative pore-forming mutant of MCU-S, termed MCU-S-DN) significantly facilitated actin cytoskeleton reorganization and morphological changes (size and complexity) after thrombin stimulation, which is critical for the activation of aggregation/coagulation pathways in platelets. Conclusions: Short MCU variant forms a Ca 2+ -permeable channel at the PM of platelets and participates in cellular Ca 2+ signaling. Elucidating the role of MCU variants provides novel insights into the molecular basis of Ca 2+ -dependent activation of platelet aggregation/coagulation pathways. Funding: The work was partially supported by NIH/NHLBI R01HL160699 (to B.S.J.), NIH/NHLBI R01HL171710 (B.S.J. and J.O.-U.), and NIH/NHLBI R01HL136757 (to J.O.-U.). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Bae et al. (Fri,) studied this question.