Mitochondria dock directly onto nuclear pores to fuel the cell nucleus

Mitochondrial function declines with age, and mitochondria influence far more than energy production. They communicate with other organelles, including the endoplasmic reticulum, to regulate calcium and redox balance. How they supply and coordinate energy-dependent processes inside the nucleus, such as chromatin regulation and gene expression, has been less clear.

This study asked whether mitochondria physically interact with the nuclear pore complex. The researchers used two unbiased proteomic approaches, GST pulldown and BioID proximity labeling, to identify mitochondrial proteins that bind nuclear pore components. They then manipulated the interaction using RANBP2 CRISPR knockout, truncation, and site-directed mutagenesis in cells, and a C-terminal RANBP2 deletion in mice.

VDAC1, an outer mitochondrial membrane channel, emerged as the top mitochondrial candidate interacting with RANBP2, a filamentous protein on the nuclear pore. Disrupting this interaction reduced mitochondria-nucleus proximity and lowered nuclear ATP and phosphocreatine. The nuclear phosphoproteome declined, and pathways for histone modification, cellular differentiation, and transcriptional regulation were downregulated. In mice, losing the RANBP2 C-terminal domain caused embryonic lethality linked to cardiac and neural crest differentiation defects.

The work proposes a mechanism by which mitochondria directly support nuclear energetics and thereby cell fate decisions. For longevity research, it points to a possible link between mitochondrial health, nuclear energy supply, and epigenetic or transcriptional regulation, though this is a hypothesis for future testing.

Caveats: this summary is based only on the abstract. The data come from cell models and embryonic mouse development, not aging or human studies. Whether this interaction changes with age, or can be therapeutically targeted, remains unknown, and the authors note additional roles are yet to be discovered.