Researchers at the Center for Genomic Regulation (CRG) have uncovered surprising findings that reshape our understanding of cellular functions. Metabolic enzymes, traditionally associated with energy production and nucleotide synthesis in mitochondria, have been found to perform critical “second jobs” within the nucleus. These discoveries were reported in two separate studies published in Nature Communications and reveal new layers of complexity in cellular biology that may have significant implications for cancer therapies, especially in aggressive cancers like triple-negative breast cancer (TNBC).
For decades, biology textbooks have neatly classified cellular components: mitochondria are described as the powerhouses generating cellular energy, the cytoplasm is where protein synthesis and metabolic reactions occur, and the nucleus is the keeper of genetic information. However, Dr. Sara Sdelci and her team at CRG have demonstrated that these functional boundaries are more fluid than previously believed. The team discovered that certain metabolic enzymes, known for their activities in the cytoplasm and mitochondria, also operate within the nucleus, taking on entirely different roles essential to maintaining cellular integrity.
Dr. Sdelci, the lead author of the studies, explains that the situation is akin to discovering that a local baker is also a skilled brewer—though they use overlapping skills, they are performing completely distinct tasks in different environments. The research team has shown that the secondary roles of these enzymes in the nucleus are just as critical as their primary metabolic functions, adding a new dimension to our understanding of cellular organization.
One of the studies focused on the enzyme MTHFD2, which is typically found in mitochondria where it supports cell growth by synthesizing key cellular building blocks. Research led by Dr. Natalia Pardo Lorente revealed that MTHFD2 also operates within the nucleus, where it is crucial for proper cell division. This is the first time scientists have demonstrated that the nucleus, beyond being a storage space for genetic material, has its own metabolic needs. Dr. Pardo Lorente emphasized that this finding fundamentally changes how we perceive the nucleus, highlighting that it actively relies on specific metabolic pathways to maintain genomic stability.
The second study, conducted by researchers Dr. Marta García-Cao and Dr. Lorena Espinar, explored the implications of these findings in cancer, particularly focusing on TNBC. This aggressive form of breast cancer is known for its resilience against standard treatments, partly due to its ability to accumulate DNA damage without triggering cell death. The researchers discovered that another enzyme, IMPDH2, plays a crucial role here. Traditionally involved in nucleotide synthesis, IMPDH2 was found to relocate to the nucleus of TNBC cells, where it assists in DNA repair, effectively preventing the damage from overwhelming the cancer cells.
Dr. García-Cao explained that IMPDH2 acts like a repair mechanic within the nucleus, controlling the DNA damage response and thereby enhancing the cancer cells’ survival. However, the team discovered a way to exploit this mechanism. By artificially increasing the levels of IMPDH2 in the nucleus, they overwhelmed the cancer cells’ repair systems, causing them to self-destruct. Dr. Espinar likened this strategy to overloading an already sinking ship with more water, causing it to sink faster.
These findings have significant implications for cancer therapy. The study on IMPDH2 also explored its interaction with PARP1, a protein targeted by existing cancer drugs known as PARP inhibitors. By targeting both IMPDH2 and PARP1, the researchers suggest that it may be possible to develop a new biomarker that can predict which tumors will respond better to treatment with PARP inhibitors. This could help tailor therapies more effectively for patients with TNBC, a form of cancer that currently has limited treatment options.
Dr. Sdelci believes that targeting these “moonlighting” metabolic enzymes could become a novel therapeutic strategy. The idea is to simultaneously disrupt cancer cells’ energy production while impairing their ability to repair DNA, making them more vulnerable to traditional treatments. This two-pronged approach could help overcome cancer’s notorious ability to develop resistance to drugs, providing a potential advantage in treating aggressive cancers.
While the concept of enzymes having multiple roles within a cell is not entirely new, these studies highlight just how extensive and crucial these secondary functions can be. According to Dr. Pardo Lorente, this represents a significant shift in our understanding of cellular organization. The realization that metabolic enzymes can serve dual functions within different cellular compartments opens up exciting possibilities for future research and therapeutic interventions.
Dr. Sdelci notes that this discovery could be just the beginning. The findings suggest that many more metabolic enzymes may have similarly hidden roles in cellular processes, waiting to be uncovered. This new perspective underscores a more interconnected view of cellular functions, offering new insights not just into the biology of cancer but potentially into other diseases where cellular metabolism plays a key role.
More information: Nuclear localization of MTHFD2 is required for correct mitosis progression, Nature Communications (2024). DOI: 10.1038/s41467-024-51847-z
Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity, Nature Communications (2024). DOI: 10.1038/s41467-024-53877-z
Source: Center for Genomic Regulation