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Ischemia-induced metabolic remodeling plays a critical role in the pathogenesis of adverse cardiac remodeling and heart failure however, the underlying molecular mechanism is largely unknown. Here, we assess the potential roles of nicotinamide riboside kinase-2 (NRK-2), a muscle-specific protein, in ischemia-induced metabolic switch and heart failure through employing transcriptomic and metabolomic approaches in ischemic NRK-2 knockout mice. The investigations revealed NRK-2 as a novel regulator of several metabolic processes in the ischemic heart. Cardiac metabolism and mitochondrial function and fibrosis were identified as top dysregulated cellular processes in the KO hearts post-MI. Several genes linked to mitochondrial function, metabolism, and cardiomyocyte structural proteins were severely downregulated in the ischemic NRK-2 KO hearts. Analysis revealed significantly upregulated ECM-related pathways which was accompanied by the upregulation of several key cell signaling pathways including SMAD, MAPK, cGMP, integrin, and Akt in the KO heart post-MI. Metabolomic studies identified profound upregulation of metabolites mevalonic acid, 3,4-dihydroxyphenylglycol, 2-penylbutyric acid, and uridine. However, other metabolites stearic acid, 8,11,14-eicosatrienoic acid, and 2-pyrrolidinone were significantly downregulated in the ischemic KO hearts. Taken together, these findings suggest that NRK-2 promotes metabolic adaptation in the ischemic heart. The aberrant metabolism in the ischemic NRK-2 KO heart is largely driven by dysregulated cGMP and Akt and mitochondrial pathways. Key messages: Post-myocardial infarction metabolic switch critically regulates the pathogenesis of adverse cardiac remodeling and heart failure. Here, we report NRK-2 as a novel regulator of several cellular processes including metabolism and mitochondrial function post-MI. NRK-2 deficiency leads to downregulation of genes important for mitochondrial pathway, metabolism, and cardiomyocyte structural proteins in the ischemic heart. It was accompanied by upregulation of several key cell signaling pathways including SMAD, MAPK, cGMP, integrin, and Akt and dysregulation of numerous metabolites essential for cardiac bioenergetics. Taken together, these findings suggest that NRK-2 is critical for metabolic adaptation of the ischemic heart. [ABSTRACT FROM AUTHOR]

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]