So much for the “beneficial” lactate – an argument I have had with numerous doctors and biochemists. The issue at hand goes well beyond academic arguments. Namely, the so-called “Ringer lactate” solution is commonly given in hospitals to critically ill patients (many of them with acute kidney injury) in order to “speed up” their recovery. The study below shows that injury leads to accumulation of lactate due to increase in anaerobic glycolysis, which is upregulated in states of acute stress/injury. Far from being a passive biomarker of said injury, the accumulation of lactate was sufficient to inhibit OXPHOS (and more specifically, the Krebs cycle), and the reduction in OXPHOS is what prevented the cells from recovering. Arguably, this is what leads to the conversion of acute kidney injury (reversible, according to medicine) to the chronic version of the condition (irreversible, according to medicine). Chronic kidney disease (CKD) is one of the most common co-morbidity, especially in patients with diabetes type II and is a leading cause of death in such patients. The good news is that a simple intervention that inhibited lactate synthesis by lactate dehydrogenase (LDH), was able to effectively block the pathological process and largely reverse the (kidney) injury. The totality of evidence available so far strongly suggests that the same process is at play in many other conditions, both acute and chronic, and thus simple anti-lactate interventions such as vitamins B1 and B3 may be highly therapeutic, especially in conditions with acknowledged lactate overload such as cancer.
https://doi.org/10.1007/s00018-026-06402-y
https://bioengineer.org/lactate-overload-blocks-kidney-recovery-by-crippling-mitochondria-through-mrs2/
“…Acute kidney injury, or AKI, affects a substantial share of hospitalized patients and carries significant short-term mortality and long-term risk of chronic kidney disease. At the cellular level, the damage concentrates in the proximal tubular epithelial cells, the workhorse cells of the nephron that normally rely overwhelmingly on mitochondrial oxidative phosphorylation to power massive reabsorption of solutes. When ischemia cuts off oxygen, these cells suffer a bioenergetic collapse: ATP production plummets, mitochondrial homeostasis is disrupted, and the tricarboxylic acid cycle, the central hub of oxidative metabolism, grinds toward inactivity. In a desperate bid to survive, the cells pivot to glycolysis, generating ATP from glucose without oxygen. That metabolic switch produces lactate as its signature byproduct, and lactate accumulation has long been regarded as a passive marker of the injury. The new study asks a sharper question: is lactate merely a bystander, or is it an active driver of the mitochondrial failure that follows?”
“…To answer it, the researchers assembled evidence from three complementary systems: human renal biopsy specimens from patients with AKI, a murine model of ischemia/reperfusion-induced AKI, and proximal tubular epithelial cells challenged in vitro with hypoxia followed by reoxygenation. Across all three, they documented the same sequence. Ischemia/reperfusion inflicted a pronounced bioenergetic deficit in the proximal tubules, characterized by disrupted mitochondrial homeostasis, suppressed activity of TCA cycle genes, and enhanced aerobic glycolysis. Crucially, the lactate that accumulated during reperfusion was not inert. When the team blocked lactate production with sodium oxamate, a well-established inhibitor of lactate dehydrogenase, tubular injury was attenuated and oxidative metabolism was partially restored, indicating that lactate actively impairs mitochondrial oxidative metabolism rather than simply reflecting it.”
“…That overload, the study found, inhibits citrate synthase, the enzyme that catalyzes the first committed step of the TCA cycle. The consequence is a vicious loop: glycolysis generates lactate, lactate triggers MRS2-mediated magnesium influx, magnesium excess throttles the TCA cycle, and the crippled oxidative machinery forces the cell to lean even harder on glycolysis, producing more lactate. Technical measurements anchored the claim. The team assessed mitochondrial function and oxidative metabolism using oxygen consumption rate assays, which quantify how efficiently mitochondria consume oxygen to generate ATP, alongside direct measurements of ATP production, mitochondrial membrane potential, and expression of TCA cycle genes. In the injured tubules, these readouts collapsed in parallel with rising lactate and rising MRS2 activity. When MRS2 was suppressed, either pharmacologically with the inhibitor CPACC or genetically with siRNA, mitochondrial oxidative metabolism rebounded, lactate accumulation fell, and renal injury following ischemia/reperfusion was attenuated.”
