Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites

<jats:p>Mitochondria relay their functional state to the nucleus via retrograde signaling, yet whether the spatial organization of the mitochondrial network plays a role in this process remains unclear. Here, we show that stress–induced clustering of mitochondria around the nucleus is a crucial part of the retrograde response. Perinuclear clustering facilitates the formation of mitochondria–nucleus contact sites (MNCS) and the nuclear entry of GPS2, a key mediator of mitochondrial retrograde signaling essential for activating nuclear–encoded mitochondrial and stress–response genes in response to various mitochondrial stressors. Unexpectedly, TSPO-driven MNCS are dispensable for GPS2–based retrograde signaling. Instead, we identify the mitochondrial import receptor TOMM70 and the nucleoporin RanBP2/NUP358 as components of a stress–induced nuclear pore–associated tethering complex required for promoting GPS2 nuclear translocation and activation of downstream programs. These findings establish MNCS as a functional gateway for mitochondrial retrograde signaling, highlighting that organelle positioning and tethering at the nuclear pore provide an unexpected layer of stress regulation.</jats:p>