Altered expression levels of the long noncoding RNA (lncRNA) nuclear‐enriched abundant transcript 1 (NEAT1) have been reported in different types of cancer. More than half of the NEAT1 studies in cancer have been published within the last 2 years. In this review, we discuss very recent developments and insights into NEAT1 contribution to carcinogenesis. Summarizing the literature, it becomes obvious that NEAT1 is a lncRNA highly de‐/upregulated in a variety of cancer entities, in which it primarily acts as a competing endogenous RNA (ceRNA) which sponges tumor‐suppressive microRNA (miRNA). The sponged miRNA lose their ability to degrade, silence, or hamper translation of their downstream—mostly oncogenic—target transcripts, ultimately promoting carcinogenesis. This role of NEAT1 function in tumorigenesis suggests it may be a prognostic biomarker as well as potential therapeutic target, pending the completion of further studies into the underlying mechanisms.

Recently identified core proteins (MICU1, MCU, EMRE) forming the mitochondrial Ca 2+ uniporter complex propelled investigations into its physiological workings. Here, we apply structured illumination microscopy to visualize and localize these proteins in living cells. Our data show that MICU1 localizes at the inner boundary membrane (IBM) due to electrostatic interaction of its polybasic domain. Moreover, this exclusive localization of MICU1 is important for the stability of cristae junctions (CJ), cytochrome c release and mitochondrial membrane potential. In contrast to MICU1, MCU and EMRE are homogeneously distributed at the inner mitochondrial membrane under resting conditions. However, upon Ca 2+ elevation MCU and EMRE dynamically accumulate at the IBM in a MICU1-dependent manner. Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework.

Summary Reprogramming of metabolic pathways determines cell functions and fate. In our work, we have used organelle-targeted ATP biosensors to evaluate cellular metabolic settings with high resolution in real time. Our data indicate that mitochondria dynamically supply ATP for glucose phosphorylation in a variety of cancer cell types. This hexokinase-dependent process seems to be reversed upon the removal of glucose or other hexose sugars. Our data further verify that mitochondria in cancer cells have increased ATP consumption. Similar subcellular ATP fluxes occurred in young mouse embryonic fibroblasts (MEFs). However, pancreatic beta cells, senescent MEFs, and MEFs lacking mitofusin 2 displayed completely different mitochondrial ATP dynamics, indicative of increased oxidative phosphorylation. Our findings add perspective to the variability of the cellular bioenergetics and demonstrate that live cell imaging of mitochondrial ATP dynamics is a powerful tool to evaluate metabolic flexibility and heterogeneity at a single-cell level.

Background/Aims: Resveratrol and its derivate piceatannol are known to induce cancer cell-specific cell death. While multiple mechanisms of actions have been described including the inhibition of ATP synthase, changes in mitochondrial membrane potential and ROS levels, the exact mechanisms of cancer specificity of these polyphenols remain unclear. This paper is designed to reveal the molecular basis of the cancer-specific initiation of cell death by resveratrol and piceatannol. Methods: The two cancer cell lines EA.hy926 and HeLa, and somatic short-term cultured HUVEC were used. Cell viability and caspase 3/7 activity were tested. Mitochondrial, cytosolic and endoplasmic reticulum Ca²⁺ as well as cytosolic and mitochondrial ATP levels were measured using single cell fluorescence microscopy and respective genetically-encoded sensors. Mitochondria-ER junctions were analyzed applying super-resolution SIM and ImageJ-based image analysis. Results: Resveratrol and piceatannol selectively trigger death in cancer but not somatic cells. Hence, these polyphenols strongly enhanced mitochondrial Ca²⁺ uptake in cancer exclusively. Resveratrol and piceatannol predominantly affect mitochondrial but not cytosolic ATP content that yields in a reduced SERCA activity. Decreased SERCA activity and the strongly enriched tethering of the ER and mitochondria in cancer cells result in an enhanced MCU/Letm1-dependent mitochondrial Ca²⁺ uptake upon intracellular Ca²⁺ release exclusively in cancer cells. Accordingly, resveratrol/piceatannol-induced cancer cell death could be prevented by siRNA-mediated knock-down of MCU and Letm1. Conclusions: Because their greatly enriched ER-mitochondria tethering, cancer cells are highly susceptible for resveratrol/piceatannol-induced reduction of SERCA activity to yield mitochondrial Ca²⁺ overload and subsequent cancer cell death.

Recent studies revealed that mitochondrial Ca2+ channels, which control energy flow, cell signalling and death, are macromolecular complexes that basically consist of the pore-forming mitochondrial Ca2+ uniporter (MCU) protein, the essential MCU regulator (EMRE), and the mitochondrial Ca2+ uptake 1 (MICU1). MICU1 is a regulatory subunit that shields mitochondria from Ca2+ overload. Before the identification of these core elements, the novel uncoupling proteins 2 and 3 (UCP2/3) have been shown to be fundamental for mitochondrial Ca2+ uptake. Here we clarify the molecular mechanism that determines the UCP2/3 dependency of mitochondrial Ca2+ uptake. Our data demonstrate that mitochondrial Ca2+ uptake is controlled by protein arginine methyl transferase 1 (PRMT1) that asymmetrically methylates MICU1, resulting in decreased Ca2+ sensitivity. UCP2/3 normalize Ca2+ sensitivity of methylated MICU1 and, thus, re-establish mitochondrial Ca2+ uptake activity. These data provide novel insights in the complex regulation of the mitochondrial Ca2+ uniporter by PRMT1 and UCP2/3.