PDF(Pubmed)
Abstract：
Little is known about the effects of statins, which are cholesterol-lowering drugs, on the bioenergetic functions of mitochondria in the brain. This study aimed to elucidate the direct effects of atorvastatin and simvastatin on the bioenergetics of isolated rat brain mitochondria by measuring the statin-induced changes in respiratory chain activity, ATP synthesis efficiency, and the production of reactive oxygen species (ROS). Our results in isolated brain mitochondria are the first to demonstrate that atorvastatin and simvastatin dose-dependently significantly inhibit the activity of the mitochondrial respiratory chain, resulting in a decreased respiratory rate, a decreased membrane potential, and increased ROS formation. Moreover, the tested statins reduced mitochondrial coupling parameters, the ADP/O ratio, the respiratory control ratio, and thus, the oxidative phosphorylation efficiency in brain mitochondria. Among the oxidative phosphorylation complexes, statin-induced mitochondrial impairment concerned complex I, complex III, and ATP synthase activity. The calcium-containing atorvastatin had a significantly more substantial effect on isolated brain mitochondria than simvastatin. The higher inhibitory effect of atorvastatin was dependent on calcium ions, which may lead to the disruption of calcium homeostasis in mitochondria. These findings suggest that while statins are effective in their primary role as cholesterol-lowering agents, their use may impair mitochondrial function, which may have consequences for brain health, particularly when mitochondrial energy efficiency is critical.
摘要：
对他汀类药物的作用知之甚少，是降胆固醇的药物，大脑中线粒体的生物能量功能。这项研究旨在通过测量他汀类药物诱导的呼吸链活性变化来阐明阿托伐他汀和辛伐他汀对离体大鼠脑线粒体生物能学的直接影响。ATP合成效率，和活性氧（ROS）的产生。我们在分离的脑线粒体中的结果首次证明阿托伐他汀和辛伐他汀剂量依赖性地显著抑制线粒体呼吸链的活性，导致呼吸频率下降，膜电位降低，并增加ROS的形成。此外，测试的他汀类药物降低了线粒体偶联参数，ADP/O比，呼吸控制率，因此，脑线粒体的氧化磷酸化效率。在氧化磷酸化复合物中，他汀类药物诱导的线粒体损伤与复合物I有关，复杂III，和ATP合酶活性。与辛伐他汀相比，含钙的阿托伐他汀对离体脑线粒体的影响明显更大。阿托伐他汀的较高抑制作用依赖于钙离子，这可能导致线粒体钙稳态的破坏。这些发现表明，虽然他汀类药物作为降胆固醇药物的主要作用是有效的，它们的使用可能会损害线粒体功能，这可能会对大脑健康产生影响，特别是当线粒体能量效率至关重要时。
