Chronic Lactate Exposure Decreases Mitochondrial Function by Inhibition of Fatty Acid Uptake and Cardiolipin Alterations in Neonatal Rat Cardiomyocytes.
Chronic Lactate Exposure Decreases Mitochondrial Function by Inhibition of Fatty Acid Uptake and Cardiolipin Alterations in Neonatal Rat Cardiomyocytes.
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DOI：
10.3389/fnut.2022.809485
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发表时间：
2022
影响因子：
5
通讯作者：
Brooks GA
中科院分区：
文献类型：
--
作者：
San-Millan I;Sparagna GC;Chapman HL;Warkins VL;Chatfield KC;Shuff SR;Martinez JL;Brooks GA
乳酸是一种重要的信号分子，具有自分泌、旁分泌和内分泌特性，参与多种生物过程，包括基因表达和代谢的调节。在心力衰竭、2 型糖尿病和癌症等与心脏代谢疾病相关的疾病中，乳酸水平会长期升高。使用新生儿心室肌细胞，我们测试了这样的假设：慢性乳酸暴露可能会降低心脏线粒体的活性，从而导致心脏和其他组织的代谢不灵活。用 5、10 或 20 mM 乳酸处理新生大鼠心室肌细胞 (NRVM) 48 小时，并使用放射性标记测定法测试 CPT I 和 II 活性。使用电喷雾电离质谱法、Amplex Red 测量的活性氧 (ROS) 水平以及 Seahorse 分析仪测量的线粒体耗氧量，确定了主要线粒体磷脂（心磷脂）的分子种类谱。随着乳酸暴露，CPT I 活性呈下降趋势 (p = 0.07)，CPT II 活性显着降低 (p < 0.001)。含有 4 个 18 个碳链（总共 72 个碳）的心磷脂分子种类随着乳酸暴露而增加，但其他大小的种类显着减少。此外，乳酸会强烈增强ROS的产生（p < 0.001），而线粒体ATP的产生和最大呼吸均会随着乳酸的暴露而显着下调（分别为p < 0.05和p < 0.01）。心肌细胞中的慢性乳酸暴露会导致脂肪酸运输减少、心磷脂重塑改变、ROS 产生增加和线粒体耗氧量减少，这可能对代谢健康和灵活性产生影响。细胞内或细胞外乳酸水平在心脏代谢疾病、心力衰竭和其他形式的代谢不灵活中发挥作用的可能性需要在体内进行评估。
Lactate is an important signaling molecule with autocrine, paracrine and endocrine properties involved in multiple biological processes including regulation of gene expression and metabolism. Levels of lactate are increased chronically in diseases associated with cardiometabolic disease such as heart failure, type 2 diabetes, and cancer. Using neonatal ventricular myocytes, we tested the hypothesis that chronic lactate exposure could decrease the activity of cardiac mitochondria that could lead to metabolic inflexibility in the heart and other tissues. Neonatal rat ventricular myocytes (NRVMs) were treated for 48 h with 5, 10, or 20 mM lactate and CPT I and II activities were tested using radiolabelled assays. The molecular species profile of the major mitochondrial phospholipid, cardiolipin, was determined using electrospray ionization mass spectrometry along with reactive oxygen species (ROS) levels measured by Amplex Red and mitochondrial oxygen consumption using the Seahorse analyzer. CPT I activity trended downward (p = 0.07) and CPT II activity significantly decreased with lactate exposure (p < 0.001). Cardiolipin molecular species containing four 18 carbon chains (72 carbons total) increased with lactate exposure, but species of other sizes decreased significantly. Furthermore, ROS production was strongly enhanced with lactate (p < 0.001) and mitochondrial ATP production and maximal respiration were both significantly down regulated with lactate exposure (p < 0.05 and p < 0.01 respectively). Chronic lactate exposure in cardiomyocytes leads to a decrease in fatty acid transport, alterations of cardiolipin remodeling, increases in ROS production and decreases in mitochondrial oxygen consumption that could have implications for both metabolic health and flexibility. The possibility that both intra-, or extracellular lactate levels play roles in cardiometabolic disease, heart failure, and other forms of metabolic inflexibility needs to be assessed in vivo.
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DOI：
10.1152/ajpendo.00142.2017
发表时间：
2018-02-01
影响因子：
5.1
作者：
Bergman, Bryan C.;Perreault, Leigh;EcKel, Robert H.
通讯作者：
EcKel, Robert H.
影响因子：
15.9
作者：
GERTZ, EW;WISNESKI, JA;NEESE, RA
通讯作者：
NEESE, RA
影响因子：
7.7
作者：
Blaak, EE;van Aggel-Leijssen, DPC;van Baak, MA
通讯作者：
van Baak, MA
影响因子：
5
作者：
Brooks GA
通讯作者：
Brooks GA
DOI：
10.1152/ajpendo.1999.277.1.e81
发表时间：
1999-07-01
影响因子：
5.1
作者：
Bergman, BC;Butterfield, GE;Brooks, GA
通讯作者：
Brooks, GA