Mitochondria Directly Interact with the Nuclear Pore Complex

Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example is contact with the endoplasmic reticulum at mitochondrial-associated ER membranes (MAMs)1, which control pathways including redox and calcium homeostasis2,3. Recent studies also reported direct mitochondria–nuclear membrane contacts in cancer cells and yeast that promote pro-survival signaling4,5. Here, we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knock-out, RANBP2 truncation, or site directed mutagenesis of RANBP2-VDAC1 interacting amino acids 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, cellular 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 critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interact remain to be revealed.