Maintaining homeostasis of Ca(2+) stores in the endoplasmic reticulum (ER) is crucial for proper Ca(2+) signaling and key cellular functions. The Ca(2+)-release-activated Ca(2+) (CRAC) channel is responsible for Ca(2+) influx and refilling after store depletion, but how cells cope with excess Ca(2+) when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca(2+) stores from overfilling, acting as what we term a "Ca(2+) load-activated Ca(2+) channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca(2+) overloading and disassembly upon Ca(2+) depletion and forms a Ca(2+)-selective ion channel on giant liposomes. TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca(2+) in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca(2+) ions.

Background: Oxidative damage has been implicated in the pathology of Huntington disease (HD). Results: Strikingly higher mitochondrial Ca 2ϩ loading and superoxide generation cause significantly higher levels of mitochondrial DNA damage in HD cells. Conclusion: Excessive mitochondrial Ca2ϩ loading-dependent oxidant generation is a causative factor for HD. Significance: Our data reveal new links between dysregulated mitochondrial Ca 2ϩ signaling and elevated oxidative DNA damage in HD.

Europium (Eu) is often regarded as a critical mineral due to its byproduct nature, importance to lighting technologies, and global supply concentration. However, the existing indicator-based criticality assessments have limitations to capture Eu’s supply chain information and thus fall short of reflecting its true criticality. This study quantified the flows and stocks of Eu in mainland China from 1990 to 2018. Results show that: (1) China’s Eu demand decreased by 75% from 2011 to 2018, as a result of the lighting technology transition from fluorescent lamps to light-emitting diodes, which significantly reduced Eu’s importance; (2) the supply of Eu mined as a byproduct kept increasing together with the growing rare earth production, which caused a substantial supply surplus being ≈1900 t by 2018; (3) despite the leading role of China in global Eu production, Eu mined in China was exported mainly in the form of intermediate and final products, and ≈90% Eu embedded in domestically produced final products was used for export recently. This study indicates that Eu’s criticality is not as severe as previously assessed and highlights the necessity of material flow analysis for a holistic and dynamic view on the entire supply chain of critical minerals.