Research Uncovers Mitochondrial Impact on Cellular Identity Shift
Recent research has revealed that mitochondrial dysfunction can significantly alter cellular identity, a finding that could expand our understanding of cellular adaptation mechanisms. Conducted by a team led by Professor Dr. Aleksandra Trifunovic at the CECAD Cluster of Excellence for Aging Research, the study indicates that cells can respond to mitochondrial stress by modifying their metabolic pathways rather than ceasing function completely.
Using a mouse model with mitochondrial quality control defects, the researchers discovered that affected cells initiate a complex metabolic response. Instead of shutting down, these cells rewire key enzymes to produce D-2HG, a metabolite previously linked to tumor progression in certain cancers. Published in Nature Metabolism in March 2025, the study titled “2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction” highlights the metabolite’s unexpected adaptive role within this context.
Researchers found that D-2HG modifies how DNA is organized within the cell nucleus, influencing gene expression and reshaping the nuclear envelope. This process not only aids in cellular adaptation to mitochondrial dysfunction but also leads to significant changes in cellular identity and structure. As Dr. Harshita Kaul, the first author of the study, commented, “What is striking is that D-2HG, typically viewed as harmful, may have an adaptive function in certain contexts.”
The research also shed light on the lesser-known functions of mitochondria, particularly their role in maintaining the health of brown fat, a specialized tissue that regulates body temperature and metabolism. When mitochondrial function declines, brown fat can undergo a transformation into a less active state, resembling typical white fat, a process referred to as “whitening.” The study demonstrated that elevated levels of D-2HG are associated with increased whitening of brown fat, which indicates a shift in cellular identity.
Professor Trifunovic explained, “This metabolite-driven rewiring seems to run parallel to a broader stress response mechanism we call mitochondrial integrated stress response.” The findings suggest that the production of D-2HG creates a link between mitochondrial dysfunction and nuclear mechanics, broadening the understanding of how cells adapt in metabolically active tissues.
Moreover, the results indicate that the stiffness of the cell nucleus could serve as a potential marker for mitochondrial signaling, metabolic stress, and overall cellular state. This insight may lead to the development of novel diagnostic tools, particularly for metabolic disorders and age-related diseases.
Researchers are now investigating whether this pathway operates similarly in other tissues, such as the heart and brain, and how it might be targeted for therapeutic interventions. As the understanding of mitochondrial signaling evolves, it opens up new avenues for addressing various health issues linked to metabolic dysfunction.
For further details, refer to the study by Harshita Kaul et al in Nature Metabolism (2025). DOI: 10.1038/s42255-025-01332-8.
