Mitochondria are essential cellular structures responsible for energy production and stress response. When these organelles malfunction, cells must adapt to survive. A recent study using a mouse model with mitochondrial quality control defects revealed a sophisticated metabolic response in brown fat tissue. Instead of shutting down, cells rewired key enzymes to produce the metabolite D-2HG.
Published in Nature Metabolism, the study led by Professor Dr. Aleksandra Trifunovic at CECAD Cluster of Excellence uncovered how D-2HG, previously linked to tumor progression, aids in cellular adaptation to mitochondrial dysfunction. By altering DNA packaging, gene expression, and nuclear structure, D-2HG promotes tissue survival under stress while changing its identity.
Dr. Harshita Kaul, the first author of the study, noted the adaptive function of D-2HG in certain contexts, challenging the perception of its harmful nature. The research also highlighted the role of mitochondria in maintaining healthy brown fat function, crucial for regulating body temperature and metabolism.
When mitochondria fail, brown fat transitions to a less active state resembling white fat, a process known as “whitening.” Elevated D-2HG levels accelerated this transformation, indicating altered cellular identity. This metabolic rewiring, in conjunction with the mitochondrial integrated stress response, showcased the unexpected cross-talk between mitochondrial dysfunction and nuclear mechanics.
The findings suggest nuclear stiffness as a potential marker for mitochondrial signaling, metabolic stress, and cellular state, offering insights for diagnosing metabolic and age-related disorders. Future research aims to explore this pathway in other tissues like the heart and brain and investigate therapeutic targeting strategies.
For more information, refer to the study published in Nature Metabolism by Harshita Kaul et al. (DOI: 10.1038/s42255-025-01332-8). The University of Cologne provided this research, paving the way for innovative diagnostic tools and therapeutic interventions in metabolic diseases and age-related conditions.
