Pandya Jignesh D, Valdez Matthew, Royland Joyce E, MacPhail Robert C, Sullivan Patrick G, Kodavanti Prasada Rao S
Spinal Cord and Brain Injury Research Center, Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA.
Oak Ridge Institute for Science and Education, U.S. Department of Energy, Oak Ridge, TN 37831, USA.
J Aging Res. 2020 Apr 1;2020:7232614. doi: 10.1155/2020/7232614. eCollection 2020.
Mitochondria play a central role in energy homeostasis and act as regulatory checkpoints for downstream metabolic responses and cell senescence processes during an entire life span. Acute or chronic environmental toxicant exposures have shown deleterious organ-specific human health issues at various life stages. Since mitochondria are a prime target for ensuing cellular bioenergetics responses and senescence, it is essential to understand mitochondrial bioenergetic responses in different organs over multiple life stages. Therefore, in the present study, we evaluated mitochondrial bioenergetic parameters in the liver, lung, and heart in four diverse age groups (young: 1 month; adult: 4 months; middle-aged: 12 months; old-aged: 24 month) using male Brown Norway rats as a model of aging ( = 5 sample size/organ/age group) and compared them with our previously published results on brain. Real-time mitochondrial bioenergetic parameters (i.e., State III, State IV, and State V) were measured using the Seahorse Extracellular Flux Analyzer. Additionally, mitochondrial enzyme pyruvate dehydrogenase complex (PDHC), Complex I, Complex II, and Complex IV activities were measured using Synergy HT plate reader. Our results indicated that nearly in all parameters, significant age- and organ-specific interactions were observed. We observed age-specific declines in State III (i.e., ATP synthesis rate) responses in both the heart and lung, where opposite was observed in the liver as age advances. Across the age, the heart has highest enzyme activities than the liver and lung. Interestingly, heart and liver mitochondrial bioenergetic rates and enzyme activities remain higher than the lung, which specifies their higher metabolic capabilities than the lung. Amongst all, bioenergetic rates and enzyme activities in the lung remain lowest suggesting the lung may display higher vulnerability and lower resilience to environmental toxicants during aging than other organs tested here. Overall, these age- and organ-specific findings may facilitate a more contextualized understanding of mitochondrial bioenergetic outcomes when considering the interactions of age-related sensitivities with exposure to chemical stressors from the environment.
线粒体在能量稳态中发挥核心作用，并在整个生命周期中作为下游代谢反应和细胞衰老过程的调节控制点。急性或慢性环境毒物暴露已在不同生命阶段显示出有害的器官特异性人类健康问题。由于线粒体是随后细胞生物能量反应和衰老的主要靶点，因此了解不同器官在多个生命阶段的线粒体生物能量反应至关重要。因此，在本研究中，我们以雄性棕色挪威大鼠作为衰老模型（每个器官/年龄组样本量n = 5），评估了四个不同年龄组（幼年：1个月；成年：4个月；中年：12个月；老年：24个月）的肝脏、肺和心脏中的线粒体生物能量参数，并将其与我们之前发表的关于大脑的结果进行了比较。使用海马细胞外通量分析仪测量实时线粒体生物能量参数（即状态III、状态IV和状态V）。此外，使用Synergy HT多功能酶标仪测量线粒体酶丙酮酸脱氢酶复合体（PDHC）、复合体I、复合体II和复合体IV的活性。我们的结果表明，几乎在所有参数中，都观察到了显著的年龄和器官特异性相互作用。我们观察到心脏和肺中状态III（即ATP合成速率）反应存在年龄特异性下降，而随着年龄增长，肝脏中则观察到相反的情况。在各个年龄段中，心脏的酶活性高于肝脏和肺。有趣的是，心脏和肝脏的线粒体生物能量速率和酶活性仍然高于肺，这表明它们的代谢能力比肺更高。在所有器官中，肺的生物能量速率和酶活性最低，这表明在衰老过程中，肺可能比这里测试的其他器官对环境毒物表现出更高的脆弱性和更低的恢复力。总体而言，这些年龄和器官特异性的发现可能有助于在考虑年龄相关敏感性与环境化学应激源暴露之间的相互作用时，更全面地理解线粒体生物能量结果。
