Abstract Body: Mitochondria can regulate cellular processes through direct and indirect interactions with various cellular components and organelles. Direct mitochondria interactions have been described in relation to the endoplasmic reticulum (ER) where distinct structures called mitochondrial-associated ER membranes (MAMs) regulate numerous cellular processes including redox and calcium homeostasis. Importantly, recent elegant reports described direct interaction between mitochondria and nuclear membranes in cancer cells and yeast, which appear to regulate pro-survival signaling. While these contact sites tether the nuclear and mitochondrial membranes, it remains unclear how cargo exchange between the mitochondria and the nucleus occurs through their impermeable membranes.. Here, we describe the existence of direct interactions between the nuclear pore and the mitochondria. In two unbiased proteomic screens, GST pulldown and BioID, VDAC1 was the top mitochondrial candidate that interacts with the nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knock-out, RANBP2 truncation, or site directed mutagenesis of RANBP2-interacting amino acids in VDAC1 resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in levels of the nuclear phosphoproteome, and downregulation of pathways involved in histone modification, cardiomyocyte differentiation and transcriptional regulation in vitro. Moreover, deletion of RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the NPC, a phenomenon which is critical for regulation nuclear energetics and cellular differentiation during embryonic development, and cardiomyocyte differentiation.