An international consortium of scientists, in which the Spanish National Center for Cardiovascular Research (CNIC) has participated, has identified for the first time a mechanism by which mitochondria directly supply energy to the cell nucleus.
The work, published in the journal "Nature", demonstrates that mitochondria, considered the cellular powerhouses, physically couple to the nucleus, the main command center of the cell, through their entry gates: the nuclear pore complexes. These pores are tiny openings that allow extremely selective passage of proteins and nucleic acids into and out of the nucleus.
According to the results, this union establishes a very efficient circuit for delivering energy and metabolites directly to the nucleus. The system acts as if it were an exclusive electrical cable connected to the control center. This data challenges the classic idea that products generated by mitochondria, such as ATP, are freely dispersed throughout the cytoplasm until they reach the nucleus.
The researchers emphasize that there is a very close functional relationship between mitochondria and the nucleus. The nucleus encodes most of the essential proteins for mitochondrial function, while mitochondria provide the energy and metabolites that allow the cell to carry out its functions. Until now, it was thought that these compounds reached the nucleus by passive diffusion through the cytoplasm; however, the new work demonstrates that both organelles have developed a much more precise and direct communication system.
Using advanced microscopy techniques, proteomic analysis, genetic engineering tools, and different experimental models, the team found that mitochondria anchor to nuclear pore complexes thanks to the interaction between the mitochondrial protein VDAC1 and the nuclear pore protein RANBP2. This physical contact enables the direct transfer of energy-rich molecules to the nucleus and favors essential processes such as gene expression regulation, chromatin remodeling, transcription, and cell differentiation.
The authors highlight that the accuracy of this coupling is "astonishing". When scientists separated the mitochondria just 500 nanometers from the nucleus, a distance thousands of times smaller than the thickness of a human hair, the energy supply to the nucleus practically disappeared. "Disconnecting the cable is equivalent to turning off the lights," they add.
To assess the biological relevance of this system, the group generated cellular and animal models in which the interaction between mitochondria and nuclear pores was altered, but without compromising the mitochondria's ability to produce energy.
The consequences were "drastic," they point out. Cells lacking these connections failed to differentiate correctly into cardiomyocytes, the cells responsible for cardiac contraction. Likewise, mouse embryos carrying mutations that prevented this interaction died before birth and showed severe alterations in the development of the heart and nervous system.
"I believe this is an important discovery not only for the heart, but for all types of eukaryotic cells. We have found that these contacts are present in all cell types we analyzed," indicated Hesham A. Sadek, director of the Sarver Heart Center at the University of Arizona and group leader at the Carlos III National Center for Cardiovascular Research (CNIC).
"The research possibilities that open up from these results are enormous. Practically any field studying human pathophysiology can apply our findings and analyze how they intervene in their study models," added the researcher.
For his part, Ivan Menendez-Montes, an associate professor at the University of Arizona, states that it was a "surprising and fascinating" result. "We started this project trying to understand how mitochondrial oxidants, known as ROS, reached the DNA of the nucleus and limited the heart's innate ability to repair itself. What we found was much more important. We have seen that mitochondria and the nucleus have coordinated their functioning to such an extent that they have developed a system by which the nucleus has an exclusive energy supply service," he explained.
Implications in regenerative medicine and cancer
The work is the result of eight years of collaboration, in which 38 experts from more than a dozen international centers have participated. In addition to Hesham Sadek, CNIC researchers José Antonio Enríquez, Miguel Torres, Jesús Vázquez, Fátima Sánchez-Cabo, Consuelo Marín-Vicente, Manuel José Gómez, and Enrique Calvo have contributed to the study.
The results propose a new paradigm in cell biology, showing that the nucleus is not nourished solely by passive diffusion, but receives energy through direct physical contact with mitochondria. The authors believe that deciphering how these junctions are regulated could have a relevant impact in fields such as developmental biology, regenerative medicine, cardiovascular pathologies, cancer, and aging processes.
In summary, the researchers point out that a connection too tiny to be seen with the naked eye can help understand how the heart forms, how certain diseases arise, and how our cells age. "Learning to control this mechanism could open the door to new therapeutic strategies," they conclude.