bims-miptne 2025-07-06 papers

Circ Res. 2025 Jul 01.

Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation.

Abigail Ajanel, Izabella Andrianova, Mia Kowalczyk, Javier Menéndez Pérez, Sradha R Bhatt, Irina Portier, Taylor Boone, Abigail Ballard-Kordeliski, Yasuhiro Kosaka, Dipayan Chaudhuri, David S Paul, Wolfgang Bergmeier, Frederik Denorme, Robert A Campbell.

BACKGROUND: Platelet activation relies on changes in cytoplasmic calcium flux. However, little is known about the role mitochondrial calcium flux plays in platelet activation. Activation induces release of calcium from intracellular stores, which enters the mitochondrial matrix through the MCU (mitochondrial calcium uniporter) to regulate bioenergetics and reactive oxygen species (ROS) formation, as demonstrated in other cells. However, whether MCU contributes to platelet function is unclear.
METHODS: We generated platelet-specific Mcu-deficient mice (Mcuplt-/-) and compared them to littermate wild-type controls (Mcuplt+/+). In vitro approaches assessed mitochondrial calcium flux and platelet activation responses to stimulation of immunoreceptor tyrosine-based activation motif (ITAM) receptors and GPCRs (G protein-coupled receptors). In addition, we examined in vivo hemostasis and thrombosis. We also treated human platelets with MCU inhibitors, and platelet function was assessed.
RESULTS: Mcuplt-/- platelets had significantly reduced mitochondrial calcium flux in response to activation of ITAM receptors, whereas mitochondrial calcium flux in response to GPCR activation was unchanged. Platelet aggregation was significantly reduced by ITAM activation in Mcuplt-/- platelets, but GPCR-induced aggregation was unchanged. Similar findings were observed when MCU was inhibited in human platelets. In vivo, Mcuplt-/- mice had reduced arterial thrombosis and less ischemic stroke brain injury. Hemostasis was mildly altered in Mcuplt-/- mice. Mechanistically, mitochondrial ROS generation was significantly reduced in Mcuplt-/- platelets compared with Mcuplt+/+ platelets after ITAM-dependent activation, but not GPCR activation. Reduced mitochondrial ROS was associated with decreased ITAM signaling based on p-Syk (phospho-spleen tyrosine kinase) and p-PLCγ2 (phospho-phospholipase C-gamma 2) in Mcuplt-/- platelets. Inhibiting mitochondrial ROS decreased aggregation as well as downstream ITAM signaling in Mcuplt+/+ platelets. Conversely, treating Mcuplt-/- platelets with MitoParaquat to induce mitochondrial ROS increased platelet ITAM-dependent aggregation and signaling.
CONCLUSIONS: Our data support a role for mitochondrial calcium flux in regulating ITAM-dependent platelet activation through the generation of mitochondrial ROS.

Keywords: ITAM; mitochondria; platelet; thrombosis

DOI: https://doi.org/10.1161/CIRCRESAHA.125.326443

Cell Death Dis. 2025 Jul 01. 16(1): 467

Current understanding of eryptosis: mechanisms, physiological functions, role in disease, pharmacological applications, and nomenclature recommendations.

Anton Tkachenko, Mohammad A Alfhili, Jawaher Alsughayyir, Alessandro Attanzio, Abdulla Al Mamun Bhuyan, Bożena Bukowska, Antonio Cilla, Martha A Quintanar-Escorza, Michael Föller, Ondrej Havranek, Kashif Jilani, Anatolii Onishchenko, Etheresia Pretorius, Volodymyr Prokopiuk, Ignazio Restivo, Luisa Tesoriere, Grazia Maria Virzì, Thomas Wieder.

Early studies have shown that erythrocytes have caspase-3 and caspase-8 and are capable of dying through an apoptotic-like cell death triggered by Ca2+ ionophores. This cell death is associated with apoptosis-like morphological signs, including cell shrinkage, membrane blebbing, and phosphatidylserine externalization. To emphasize that mature erythrocytes don't have the apoptotic mitochondrial machinery and distinguish this unique cell death modality from apoptosis, it was named "eryptosis". Over recent decades, our knowledge of eryptosis has been significantly expanded, providing more insights into the uniqueness of cell death pathways in erythrocytes. In this review, we aim to summarize our current understanding of eryptosis, formulate the nomenclature and guidelines to interpret results of eryptosis studies, provide a synopsis of morphological and biochemical features of eryptosis, and highlight the role of eryptosis in health and disease, including its druggability.

DOI: https://doi.org/10.1038/s41419-025-07784-w

Plant Physiol Biochem. 2025 Jun 19. pii: S0981-9428(25)00708-9. [Epub ahead of print]227 110180

Exploration of mitochondrial calcium uniporters suggested their role in abiotic stress response in bread wheat.

Nishu, Yashraaj Sharma, Deepika, Amandeep Kaur, Santosh Kumar Upadhyay.

Mitochondrial calcium uniporters (MCUs) play a crucial role in calcium transport, signaling, and homeostasis, which is vital for plant growth, development, and stress responses. In this study, we identified 17 TaMCU genes classified into seven homoeologous groups with conserved gene architecture in the bread wheat genome. The structural analysis revealed the presence of MCU domain, DVME motif, transmembrane helices, and various key amino acid residues, which are conserved across all TaMCU proteins. Each TaMCU protein consisted of a mitochondrial targeting peptide and predicted to be localized in the mitochondria. The phylogenetic and synteny analyses provided insights into their evolutionary diverged and conserved nature. Cis-regulatory element analysis suggested that TaMCU genes are involved in abiotic stress responses, involving key transcription factors such as MYB, MBS, W-box, and ERF. Protein-protein interaction study suggested that TaMCUs interact with other mitochondrial and stress-related proteins, such as MICU, PHB, and FREE1. Additionally, six miRNAs related to plant development and stress-response such as miR5384-3p, tae-miR5050 etc., exhibited interactions with a few TaMCU transcripts. RNA-seq expression profiling revealed differential expression of various TaMCU genes in tissue developmental stages and under various stress conditions. qRT-PCR under salinity and drought treatments confirmed the involvement of TaMCU1-D, TaMCU3-A, and TaMCU5-B genes in these stress conditions. These findings provide insights into the potential roles of TaMCU genes and suggest their future applications in the development of abiotic stress-resilient crop plants.

Keywords: Abiotic stress; Bread wheat; Drought; Mitochondrial calcium uniporters; Salinity

DOI: https://doi.org/10.1016/j.plaphy.2025.110180

Science. 2025 Jul 03. 389(6755): 48-52

The intracellular Ca2+ sensitivity of transmitter release in glutamatergic neocortical boutons.

Grit Bornschein, Simone Brachtendorf, Anja Reinert, Abdelmoneim Eshra, Robert Kraft, Johannes Hirrlinger, Jens Eilers, Stefan Hallermann, Hartmut Schmidt.

Synaptotagmin-1 (Syt1) and Syt2 are the main calcium (Ca2+) sensors triggering synchronous release in the brain. In this work, we studied the mechanisms mediating Syt1-triggered release from neocortical synapses. We measured the Ca2+ dependency of release in layer 5 pyramidal neuron synapses by laser photolysis of caged Ca2+. Release had high Ca2+ affinity and positive cooperativity. Measurements at cerebellar Purkinje cell synapses and kinetic models indicate substantial differences compared with Syt2-triggered release. Our results suggest that Syt1-controlled release machineries are optimized for high reliability at moderate Ca2+ elevations and high plastic controllability.

DOI: https://doi.org/10.1126/science.adp0870