During intense exercise and increased ATP demands, lactate, a byproduct of glycolysis, is rapidly produced, leading to the common belief that lactate is a metabolic waste. However, ongoing research has revealed that lactate can serve as a fuel for the mitochondrial tricarboxylic acid (TCA) cycle, contributing to wound healing and tissue regeneration. Furthermore, lactate has been demonstrated to possess additional metabolic regulatory functions, capable of reprogramming both tumor cells and immune cells.
Case 1 Lactate activates the mitochondrial electron transport chain independently of its metabolic processes
Unlike metabolic byproducts such as urea, lactate is not excreted. Lactate, being the second most abundant circulating carbon source after glucose, is either generated in the cytoplasm for ATP production or utilized in building large molecular carbon frameworks. The known metabolic functions of lactate depend on lactate dehydrogenase (LDH), raising questions among scientists about whether lactate has LDH-independent metabolic regulatory functions.
On October 24th, the research team led by Craig B. Thompson at Memorial Sloan Kettering Cancer Center published the latest findings in Molecular Cell (IF=16) with the title "Lactate activates the mitochondrial electron transport chain independently of its metabolism." The study revealed that lactate acts as a mitochondrial messenger in cells, activating the mitochondrial electron transport chain (ETC) to produce ATP, aiding cells in more efficiently utilizing lactate and reducing their dependence on glucose.
To investigate lactate's function as a carbon source, glucose in the culture medium was replaced with an equivalent amount of L-lactate. The cells were unable to maintain their vitality and proliferation under these conditions. However, when glucose concentration was limited and lactate was additionally provided, cell proliferation was restored, reducing glucose consumption. Subsequent experiments examining lactate's impact on mitochondrial respiration demonstrated that lactate could support cell growth under restricted glucose conditions by stimulating mitochondrial ATP production and inhibiting the glycolytic pathway.
Lactate stimulation of mitochondrial respiration increases use of pyruvate as a TCA substrate
Lactate exists in two optical isomeric forms, D-lactate and L-lactate. Both isomers were found to activate the mitochondrial electron transport chain (ETC) and increase the flux of pyruvate into the TCA cycle. Isotope tracing experiments revealed that the increased ETC activity was unrelated to carbon entry through the pyruvate dehydrogenase (PDH) complex. Thus, lactate initially stimulates ETC activity, followed by PDH complex activation.
The results indicate that D-lactate and L-lactate have similar effects on mitochondrial oxidative phosphorylation, PDH activation, and TCA cycle flux. However, in the cytoplasm, D-lactate cannot be metabolized to pyruvate, while L-lactate produces pyruvate and NADH mediated by lactate dehydrogenase (LDH). Excessive NADH production disrupts intracellular redox balance, inhibiting T cell proliferation. D-lactate can bypass LDH metabolism, selectively inducing mitochondrial oxidative phosphorylation, while reducing the high rate of glycolysis, enhancing T cell proliferation and effector function by avoiding frequent metabolic shifts during T cell immunotherapy preparation.
Lactate activates the PDH complex in isolated mitochondria in a dose-dependent manner and directly enters the mitochondria matrix independently of the mitochondrial pyruvate carrier
These findings highlight lactate as a primary determinant of intracellular ATP production and a crucial regulatory factor inhibiting glucose fermentation capacity in mitochondrial oxidative phosphorylation.
Case 2 Lactate production in senescent cells promotes malignant cancer progression
Cellular aging is a major risk factor for age-related diseases such as cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. Senescent cells synthesize large amounts of pro-inflammatory cytokines, chemokines, and extracellular matrix-degrading enzymes, a phenotype known as the Senescence-Associated Secretory Phenotype (SASP). The discovery of SASP provides a rational and crucial mechanism to explain why the accumulation of a small number of senescent cells during the aging process can have harmful effects on overall health. However, the specific mechanisms underlying age-related tissue homeostasis and organ functional loss remain unclear.
The study initially found a significant upregulation of PDK4 during cellular aging. Importantly, the research validated this finding in clinical samples of prostate cancer and breast cancer. The expression levels of PDK4 in cancer tissues after neoadjuvant chemotherapy were positively correlated with the degree of cellular senescence in the tumor microenvironment and negatively correlated with patient survival. Therefore, PDK4 in the tumor stroma can serve as an independent prognostic factor for clinical outcomes, predicting the risk of disease recurrence and death. Given this pathological correlation, there is reason to speculate that PDK4 may be a crucial regulatory factor in age-related diseases such as cancer progression.
Senescent cells display a distinct glucose metabolism profile.
Previous studies on the metabolism of senescent cells have shown an increase in glucose consumption and lactate production during the aging process. However, the metabolic characteristics of glucose, the primary energy source for aging cells, and its impact on the surrounding tissue homeostasis are not well understood. Therefore, the research delved into the metabolic patterns of glucose uptake in senescent cells. The results showed a significant increase in glycolysis levels in aging cells, accompanied by an increase in the production of glycolysis-related metabolites such as DHAP, GAP, and 3-PG. Furthermore, in senescent cells, the release of pyruvate and lactate into the extracellular space was significantly elevated. Interestingly, the study found that lactate in the tumor microenvironment could induce the proliferation, migration, and invasion of tumor cells.
In clinical preclinical trials, the presence of senescent cells significantly accelerated the progression of tumors, but the deletion of PDK4 slowed down tumor development. Therefore, the research focused on how drugs targeting PDK4 could affect the therapeutic response of tumors. The PDK4-specific inhibitor, PDK4-IN, combined with chemotherapy, significantly reduced lactate levels in the animal serum compared to the group treated with chemotherapy alone. In vivo data also indicated that mouse lactate levels increased only in the presence of senescent stromal cells. Thus, senescent stromal cells in the treatment-damaged microenvironment are the major source of lactate production, providing a measurable indicator in peripheral blood. Combining PDK4-targeted drugs with conventional chemotherapy enhances the tumor-killing response without causing severe systemic cytotoxic effects, and major organ functions such as the liver and kidneys remain unaffected. This highlights the feasibility and safety of this combined treatment approach, with potential for future clinical translation.
The study delineates the PDK4-mediated metabolic reprogramming in senescent cells, leading to increased production of glycolysis-related metabolites, particularly lactate. The research systematically reveals the association between cellular aging, lactate generation, and organ degeneration, as well as age-related diseases. It proposes an intervention strategy involving PDK4-targeted drugs combined with conventional chemotherapy.
References
- Cai, Xin, et al. "Lactate activates the mitochondrial electron transport chain independently of its metabolism." Molecular Cell 83.21 (2023): 3904-3920.
- Dou, Xuefeng, et al. "PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy." Nature Metabolism (2023): 1-24.
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