Nucleus-Tethered Mitochondria are essential for Ca²⁺ homeostasis

Mitochondria form dynamic membrane contact sites (MCSs) with the surrounding organelles, including the nucleus, which we termed ‘nucleus-associated mitochondria’ (NAM). In this manuscript, we report that the stoichiometry of the NAM-forming molecule TSPO is modified in neurodegeneration diseases, and the nucleus-based component of the chromatin- and lamin-binding protein thymopoietin (TMPO/LAP2) is part of the tethering complex. Furthermore, we show that the NAM-regulated distance between mitochondria and the nucleus is pivotal for the physiological cycling of Ca²⁺ in neuronal cells. On this, the transcription of Ca²⁺-regulated genes and those that dictate the spatiotemporal execution of Ca²⁺ -such as inositol-1,4,5-trisphosphate (IP3) and ryanodine (RyR) is also dependent. This data set advances our understanding of the NAM biochemistry and function, shedding light on the mechanisms that govern mitochondrial coupling with the nucleus, aiding the homeostatic transduction of cell signalling.