Figure 619

Hypoxia-induced lactic acidosis. Accumulation of lactate during hypoxia, by far the most common clinical setting of the disorder, originates from impaired mitochondrial oxidative function that reduces the availability of adenosine triphosphate (ATP) and NAD+ (oxidized nicotinamide adenine dinucleotide) within the cytosol. In turn, these changes cause cytosolic accumulation of pyruvate as a consequence of both increased production and decreased utilization. Increased production of pyruvate occurs because the reduced cytosolic supply of ATP stimulates the activity of 6-phosphofruc-tokinase (PFK), thereby accelerating glycolysis. Decreased utilization of pyruvate reflects the fact that both pathways of its consumption depend on mitochondrial oxidative reactions: oxidative decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction catalyzed by pyruvate dehydrogenase (PDH), requires a continuous supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The increased [NADH]/[NAD+] ratio (NADH refers to the reduced form of the dinucleotide) shifts the equilibrium of the lactate dehy-drogenase (LDH) reaction (that catalyzes the interconversion of pyruvate and lactate) to the right. In turn, this change coupled with the accumulation of pyruvate in the cytosol results in increased accumulation of lactate. Despite the prevailing mitochondrial dysfunction, continuation of glycolysis is assured by the cytosolic regeneration of NAD+ during the conversion of pyruvate to lactate. Provision of NAD+ is required for the oxidation of glyceraldehyde 3-phosphate, a key step in glycolysis. Thus, lactate accumulation can be viewed as the toll paid by the organism to maintain energy production during anaerobiosis (hypoxia) [14]. ADP—adenosine diphosphate; TCA cycle—tricarboxylic acid cycle.

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