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Mysterious self-repair of mitochondria: How does UPRmt save the fate of cells?
Mitochondria play a vital role in cells. In addition to producing energy, they are also the guardians of cell health. However, when proteins within mitochondria fold improperly, the cell launches a self-defense action, which we call the mitochondrial unfolded protein response (UPRmt). This reaction is not only related to the operation of cells, but also closely related to various diseases such as aging, cancer and inflammatory bowel disease. This article will explore in depth the operating mechanism of UPRmt and its impact on cell fate.
UPRmt is a cellular response to unfolded or misfolded proteins within mitochondria that helps cells restore their protein homeostasis.
UPRmt is activated when a large amount of unfolded or misfolded proteins appear in the cell. This response enables mitochondria to increase the expression of chaperone proteins and mobilize proteases to degrade proteins that fail to fold correctly. This process not only promotes protein health within cells, but also enhances the activity of antioxidant enzymes and initiates autophagy, maintaining the integrity of mitochondria and thus protecting the life of cells.
Interestingly, scientists have found that certain mutations in the mitochondrial electron transport chain can extend the lifespan of nematodes, which is directly related to the activation of UPRmt. In addition, by supplementing substances such as nicotinamide or nicotinamide riboside, the UPRmt of nematodes can also be activated, further extending their lifespan. This makes researchers full of expectations and interest in the health-care mechanism of mitochondria.
The study found that supplementation with nicotinamide riboside activated the UPRmt response in mice, demonstrating the potential of this supplement in maintaining cellular health.
Under normal circumstances, most proteins in cells are translated and folded in the cytoplasm, and chaperone proteins play a vital role in this process. However, for special organelles, such as the endoplasmic reticulum and mitochondria, they must also ensure the correct folding of proteins, otherwise it will affect the normal functioning of the cell. The UPR mechanism of the endoplasmic reticulum targets different sources of cellular stress. When cells are unable to cope with these stresses, it may trigger the cell suicide mechanism, namely apoptosis. The initiation of UPRmt is relatively simple, with ATFS-1 as the main transcription factor, which helps upregulate chaperone proteins to repair damage.
Recent studies have further explored the relationship between UPRmt and cancer. The study found that the SIRT3 axis of UPRmt can be used as a marker to identify metastatic and non-metastatic breast cancer. As cancer cells shift metabolically from oxidative phosphorylation to aerobic glycolysis, scientists hypothesize that these cancer cells rely on UPRmt to maintain mitochondrial integrity and function. More interestingly, inhibition of UPRmt, especially in the presence of ATF5, selectively kills cancer cells, making UPRmt a potential target for cancer therapy.
After multiple studies, we found that inhibition of UPRmt can effectively and selectively kill cancer cells without damaging normal cells.
In addition, compared to cancer, inflammatory bowel disease (IBD) is also closely associated with mitochondrial dysfunction. Activation of UPRmt can be observed in both mouse models of intestinal inflammation and in IBD patients, particularly in the dysfunction of intestinal stem cells and Paneth cells. This suggests that UPRmt may provide new insights and strategies in the development, progression, and treatment of inflammation.
In summary, UPRmt, as a form of mitochondrial self-repair, shows its importance in maintaining cell health. When cells face stress and challenges, UPRmt undoubtedly provides them with a way out. This makes us wonder: In future research, can we gain a deeper understanding of this mysterious mechanism in order to develop more effective disease treatments?
