Distal control of mitochondrial biogenesis and respiratory activity by extracellular lactate caused by large-scale deletion of mitochondrial DNA

Lactate is highly produced under conditions of respiratory dysfunction such as anaerobic respiration and various types of mitochondrial diseases, and it was also known as an active molecule that plays various roles both within and between cells. High levels of extracellular lactate may lead to lactic acidosis, which has been related to pathology of the mitochondrial diseases with mutated mitochondrial DNA (mtDNA). In this study, to elucidate the poorly understood molecular roles of extracellular lactate in mitochondrial regulation, we analyzed mouse B82 cells and their cybrid cells carrying mutated mtDNA with a large-scale deletion (Delta mtDNA). Inhibition of lactate production by sodium dichloroacetate (DCA) treatment improved mitochondrial respiration in cells carrying Delta mtDNA through the activation of mitochondrial biogenesis. Chronic exposure to extracellular lactate (more than 3 days) repressed mitochondrial respiration in healthy cells via calcium and CaMK signaling, leading to a decrease in PGC1 alpha-mediated mitochondrial biogenesis. These mitochondrial dysfunctions induced by the lactate treatment were repressed by pH buffering of the medium. These results suggest that lactate, produced in respiration-deficient cells, acts not only as an intracellular source of energy through the TCA cycle, but also as an extracellular messenger molecule regulating the respiratory activity of both cells carrying Delta mtDNA and the surrounding cells, which could cause whole-body repression of respiratory activity.