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The role of store‐operated Ca2+ entry (SOCE) in melanoma metastasis is highly controversial. To address this, we here examined UV‐dependent metastasis, revealing a critical role for SOCE suppression in melanoma progression. UV‐induced cholesterol biosynthesis was critical for UV‐induced SOCE suppression and subsequent metastasis, although SOCE suppression alone was both necessary and sufficient for metastasis to occur. Further, SOCE suppression was responsible for UV‐dependent differences in gene expression associated with both increased invasion and reduced glucose metabolism. Functional analyses further established that increased glucose uptake leads to a metabolic shift towards biosynthetic pathways critical for melanoma metastasis. Finally, examination of fresh surgically isolated human melanoma explants revealed cholesterol biosynthesis‐dependent reduced SOCE. Invasiveness could be reversed with either cholesterol biosynthesis inhibitors or pharmacological SOCE potentiation. Collectively, we provide evidence that, contrary to current thinking, Ca2+ signals can block invasive behavior, and suppression of these signals promotes invasion and metastasis. Synopsis: The role of STIM/Orai‐mediated store‐operated Ca2+ entry (SOCE) in melanoma is debated. This work reports a novel signaling axis linking UV exposure to cholesterol biosynthesis and suppression of SOCE, promoting aberrant cancer metabolism and invasive phenotypes.UV radiation suppresses SOCE and enhances invasiveness of melanoma cell lines in vivo.STIM‐Orai inhibition is sufficient to drive metastasis in syngeneic mice.Increased cholesterol biosynthesis is required for UV‐induced SOCE suppression and melanoma metastasis.UV‐induced SOCE reduction enhances glucose uptake and anabolic O‐GlcNAcylation, shifting melanoma cells to a more invasive phenotype.Cholesterol‐mediated SOCE suppression and increased O‐GlcNAcylation are conserved in melanoma patient explants. [ABSTRACT FROM AUTHOR]

The discovery of MICU1 as gatekeeper of mitochondrial calcium (m Ca2+) entry has transformed our understanding of m Ca2+ flux. Recent studies revealed an additional role of MICU1 as a Ca2+ sensor at MICOS (mitochondrial contact site and cristae organizing system). MICU1's presence at MICOS suggests its involvement in coordinating Ca2+ signaling and mitochondrial ultrastructure. Besides its role in Ca2+ regulation, MICU1 influences cellular signaling pathways including transcription, epigenetic regulation, metabolism, and cell death, thereby affecting human health. Here, we summarize recent findings on MICU1's canonical and noncanonical functions, and its relevance to human health and diseases. • MICU1, a mitochondrial Ca2+ sensor, plays a key role in decoding cytoplasmic Ca2+ signals. • Through the mtCU, MICU1 modulates mitochondrial Ca2+ influx. • MICU1 functions extend beyond mtCU, impacting mitochondrial ultrastructure via MICOS. • Loss of MICU1 leads to bioenergetics failure and increased susceptibility to various cell death pathways. • MICU1 mutations are linked to neuromuscular, cognitive, and cardiac impairments. [ABSTRACT FROM AUTHOR]

Summary Ca 2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU have not been established. As an approach toward understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 (Cys-97) to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural, and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca 2+ ] m uptake rate, elevated mROS, and enhanced [Ca 2+ ] m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity. [ABSTRACT FROM AUTHOR]