Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, 560-0043, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8572, Japan; Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, Fukuoka, 830-0011, Japan.
Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8572, Japan.
Pharmacol Res. 2020 Oct;160:105204. doi: 10.1016/j.phrs.2020.105204. Epub 2020 Sep 15.
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 (ΔmtDNA). Inhibition of lactate production by sodium dichloroacetate (DCA) treatment improved mitochondrial respiration in cells carrying ΔmtDNA 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 PGC1α-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 ΔmtDNA and the surrounding cells, which could cause whole-body repression of respiratory activity.
乳酸在呼吸功能障碍的情况下大量产生，如无氧呼吸和各种类型的线粒体疾病，它也被认为是一种在细胞内和细胞间发挥各种作用的活性分子。细胞外高浓度的乳酸可能导致乳酸酸中毒，这与携带突变线粒体 DNA（mtDNA）的线粒体疾病的病理学有关。在这项研究中，为了阐明细胞外乳酸在调节线粒体方面的分子作用机制，我们分析了携带大的缺失突变（ΔmtDNA）的小鼠 B82 细胞及其杂交细胞。用二氯乙酸钠（DCA）抑制乳酸的产生，通过激活线粒体生物发生，改善了携带 ΔmtDNA 的细胞中的线粒体呼吸。慢性暴露于细胞外乳酸（超过 3 天）通过钙和 CaMK 信号抑制健康细胞中的线粒体呼吸，导致 PGC1α 介导的线粒体生物发生减少。乳酸处理引起的这些线粒体功能障碍可以通过缓冲介质的 pH 值来抑制。这些结果表明，在呼吸缺陷细胞中产生的乳酸不仅可以作为 TCA 循环的细胞内能量来源，还可以作为一种细胞外信使分子，调节携带 ΔmtDNA 的细胞和周围细胞的呼吸活性，这可能导致全身呼吸活性受到抑制。
