Department of Kinesiology, University of Massachusetts Amherst, Amherst, Massachusetts, United States.
Department of Biology, University of Massachusetts Amherst, Amherst, Massachusetts, United States.
Am J Physiol Heart Circ Physiol. 2023 Nov 1;325(5):H1088-H1098. doi: 10.1152/ajpheart.00199.2023. Epub 2023 Sep 15.
Cigarette smoke exposure is a well-known risk factor for developing numerous chronic health conditions, including pulmonary disease and cardiometabolic disorders. However, the cellular mechanisms mediating the toxicity of cigarette smoke in extrapulmonary tissues are still poorly understood. Therefore, the purpose of this study was to characterize the acute dose-dependent toxicity of cigarette smoke on mitochondrial metabolism by determining the susceptibility and sensitivity of mitochondrial respiration from murine skeletal (gastrocnemius and soleus) and cardiac muscles, as well as the aorta to cigarette smoke concentrate (CSC). In all tissues, exposure to CSC inhibited tissue-specific respiration capacity, measured by high-resolution respirometry, according to a biphasic pattern. With a break point of 451 ± 235 μg/mL, the aorta was the least susceptible to CSC-induced mitochondrial respiration inhibition compared with the gastrocnemius (151 ± 109 μg/mL; = 0.008, = 2.3), soleus (211 ± 107 μg/mL; = 0.112; = 1.7), and heart (94 ± 51 μg/mL; < 0.001; = 2.6) suggesting an intrinsic resistance of the vascular smooth muscle mitochondria to cigarette smoke toxicity. In contrast, the cardiac muscle was the most susceptible and sensitive to the effects of CSC, demonstrating the greatest decline in tissue-specific respiration with increasing CSC concentration ( < 0.001, except the soleus). However, when normalized to citrate synthase activity to account for differences in mitochondrial content, cardiac fibers' sensitivity to cigarette smoke inhibition was no longer significantly different from both fast-twitch gastrocnemius and slow-twitch soleus muscle fibers, thus suggesting similar mitochondrial phenotypes. Collectively, these findings established the acute dose-dependent toxicity of cigarette smoke on oxidative phosphorylation in permeabilized tissues involved in the development of smoke-related cardiometabolic diseases. Despite numerous investigations into the mechanisms underlying cigarette smoke-induced mitochondrial dysfunction, no studies have investigated the tissue-specific mitochondrial toxicity to cigarette smoke. We demonstrate that, while aorta is least sensitive and susceptible to cigarette smoke-induced toxicity, the degree of cigarette smoke-induced toxicity in striated muscle depends on the tissue-specific mitochondrial content. We conclude that while the mitochondrial content influences cigarette smoke-induced toxicity in striated muscles, aorta is intrinsically protected against cigarette smoke-induced mitochondrial toxicity.
香烟烟雾暴露是许多慢性健康状况的已知危险因素，包括肺部疾病和心血管代谢紊乱。然而，香烟烟雾在肺外组织中引起毒性的细胞机制仍知之甚少。因此，本研究的目的是通过确定来自鼠类骨骼肌（比目鱼肌和腓肠肌）和心肌以及主动脉对香烟烟雾浓缩物（CSC）的线粒体呼吸的易感性和敏感性，来描述 CSC 对线粒体代谢的急性剂量依赖性毒性。在所有组织中，根据双相模式，通过高分辨率呼吸测定法测量的 CSC 暴露抑制了组织特异性呼吸能力。主动脉对 CSC 诱导的线粒体呼吸抑制的敏感性低于比目鱼肌（151±109μg/mL； = 0.008， = 2.3）、腓肠肌（211±107μg/mL； = 0.112； = 1.7）和心脏（94±51μg/mL； < 0.001； = 2.6），这表明血管平滑肌线粒体对香烟烟雾毒性具有内在抗性。相比之下，心肌对 CSC 的作用最敏感和最敏感，随着 CSC 浓度的增加，组织特异性呼吸的下降最大（ < 0.001，除了比目鱼肌）。然而，当用柠檬酸合酶活性来归一化以解释线粒体含量的差异时，心肌纤维对香烟烟雾抑制的敏感性不再与快肌比目鱼肌和慢肌腓肠肌纤维明显不同，因此表明类似的线粒体表型。总之，这些发现确定了香烟烟雾对参与与吸烟有关的心血管代谢疾病发展的通透性组织中氧化磷酸化的急性剂量依赖性毒性。尽管已经进行了许多关于香烟烟雾引起的线粒体功能障碍的机制的研究，但没有研究调查香烟烟雾对线粒体的组织特异性毒性。我们证明，尽管主动脉对香烟烟雾引起的毒性最不敏感和易感性，但横纹肌中香烟烟雾引起的毒性程度取决于组织特异性线粒体含量。我们得出的结论是，虽然线粒体含量会影响横纹肌中香烟烟雾引起的毒性，但主动脉本质上受到香烟烟雾引起的线粒体毒性的保护。
