Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Gdansk, Poland; Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Poland.
Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Gdansk, Poland.
Free Radic Biol Med. 2024 Aug 1;220:312-323. doi: 10.1016/j.freeradbiomed.2024.05.022. Epub 2024 May 11.
Podocytes are crucial for regulating glomerular permeability. They have foot processes that are integral to the renal filtration barrier. Understanding their energy metabolism could shed light on the pathogenesis of filtration barrier injury. Lactate has been increasingly recognized as more than a waste product and has emerged as a significant metabolic fuel and reserve. The recent identification of lactate transporters in podocytes, the expression of which is modulated by glucose levels and lactate, highlights lactate's relevance. The present study investigated the impact of lactate on podocyte respiratory efficiency and mitochondrial dynamics. We confirmed lactate oxidation in podocytes, suggesting its role in cellular energy production. Under conditions of glucose deprivation or lactate supplementation, a significant shift was seen toward oxidative phosphorylation, reflected by an increase in the oxygen consumption rate/extracellular acidification rate ratio. Notably, lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) isoforms, which are involved in lactate conversion to pyruvate, were detected in podocytes for the first time. The presence of lactate led to higher intracellular pyruvate levels, greater LDH activity, and higher LDHB expression. Furthermore, lactate exposure increased mitochondrial DNA-to-nuclear DNA ratios and resulted in upregulation of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor coactivator-1α and transcription factor A mitochondrial, regardless of glucose availability. Changes in mitochondrial size and shape were observed in lactate-exposed podocytes. These findings suggest that lactate is a pivotal energy source for podocytes, especially during energy fluctuations. Understanding lactate's role in podocyte metabolism could offer insights into renal function and pathologies that involve podocyte injury.
足细胞对于调节肾小球通透性至关重要。它们的足突是肾滤过屏障的重要组成部分。了解其能量代谢可能有助于揭示滤过屏障损伤的发病机制。乳酸已逐渐被认为不仅仅是一种废物，而是一种重要的代谢燃料和储备。最近在足细胞中发现了乳酸转运体，其表达受葡萄糖水平和乳酸的调节，这突出了乳酸的相关性。本研究探讨了乳酸对足细胞呼吸效率和线粒体动力学的影响。我们证实了足细胞中乳酸的氧化，表明其在细胞能量产生中的作用。在葡萄糖剥夺或乳酸补充的条件下，观察到向氧化磷酸化的显著转变，表现为耗氧率/细胞外酸化率比值的增加。值得注意的是，首次在足细胞中检测到参与乳酸转化为丙酮酸的乳酸脱氢酶 A（LDHA）和乳酸脱氢酶 B（LDHB）同工酶。乳酸的存在导致细胞内丙酮酸水平升高、LDH 活性增加和 LDHB 表达增加。此外，无论葡萄糖是否存在，乳酸暴露都会增加线粒体 DNA 与核 DNA 的比值，并导致过氧化物酶体增殖物激活受体共激活因子 1α和线粒体转录因子 A 的线粒体生物发生标志物的上调。在暴露于乳酸的足细胞中观察到线粒体大小和形状的变化。这些发现表明，乳酸是足细胞的重要能量来源，尤其是在能量波动期间。了解乳酸在足细胞代谢中的作用可能有助于深入了解涉及足细胞损伤的肾功能和病理。
