Power to the genome: Scientists decipher how the nucleus gets its energy

For generations, textbooks have taught that a cell’s energy simply drifts to wherever it is needed. New research shows that the cell’s most prolific consumer of energy — the nucleus — is served by something closer to a private power line.

An international team led by Ivan Menéndez-Montes, PhD, assistant professor of medicine at the University of Arizona, and Hesham A. Sadek, MD, PhD, director of the University of Arizona Sarver Heart Center, has identified a previously unknown route by which mitochondria deliver energy directly to the cell nucleus.

The study, published in Nature, shows that mitochondria — the power plants of the cell — plug directly into the nucleus — like docking a charger, running a dedicated line straight to its command center. This finding challenges the long-held assumption that energy from the mitochondria finds its way to the nucleus as it circulates through the cell. 

“This is an important discovery, not only for the heart, but across all cell types,” Sadek said. “We found these contacts in every cell type we analyzed, and they appear to be quite important for cellular differentiation and embryonic development. We think we have only scratched the surface. In the next few years, we will find out how these mito-nuclear connections can broadly influence health and disease.”

The nucleus and mitochondria have long been known to depend on each other: The nucleus encodes the proteins mitochondria need to function, while mitochondria supply the energy and building blocks that keep the cell working.

Using advanced microscopy, proteomics, genetic engineering and animal models, the researchers found that mitochondria latch onto the pores through a direct interaction between the mitochondrial protein VDAC1 and the nuclear pore protein RANBP2. That physical link channels energy-rich molecules into the nucleus, supporting gene regulation, chromatin remodeling, transcription and cell differentiation.

The arrangement proved remarkably precise. When the team pushed mitochondria just 500 nanometers away from the nucleus — a distance thousands of times finer than a human hair — the nucleus’ energy supply fell to almost nothing. To test what these contacts actually do, the researchers engineered cells and animals in which the mitochondria-nuclear pore connection was severed while leaving the mitochondria’s ability to generate energy fully intact.

The effects were striking. Cells stripped of these contacts could not properly mature into cardiomyocytes, the beating cells of the heart. Mouse embryos carrying mutations that disrupted the interaction died before birth, with severe developmental defects in both the heart and the nervous system.

“This was a surprising and fascinating result,” Menéndez-Montes said. “We set out to understand how mitochondrial oxidants, reach DNA and trigger the halt in cell division that sits at the heart of the cardiac regeneration field. What we found was even bigger: the mitochondria and the nucleus are so tightly coordinated that they’ve built the nucleus its own exclusive energy delivery service.”

The study was the result of an eight-year collaboration involving 38 scientists from institutions around the world. In addition to Sadek and Menéndez-Montes, University of Arizona Sarver Heart Center contributors included Luke Szweda, Tara Tassin, Shibani Mukherjee, Asaithamby Aroumougame, Ahmed Elghamry, Nicholas Lam, Gonzalo Gancedo-Alonso, and Hamed El-Feky.

By showing that the nucleus draws energy through direct physical contact with mitochondria rather than through diffusion alone, the findings establish a new paradigm in cell biology. The researchers say that learning how these connections are controlled could reshape work in developmental biology, regenerative medicine, cardiovascular disease, cancer and aging. This new discovery may help explain how hearts form, how disease takes hold and how cells grow old, and learning to control it could point toward new therapies.