Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
Neuroscience. 2019 May 15;406:432-443. doi: 10.1016/j.neuroscience.2019.02.033. Epub 2019 Mar 13.
Mitochondrial dysfunction has been shown to play a major role in neurodegenerative disorders such as Huntington's disease, Alzheimer's disease and Parkinson's disease. In these and other neurodegenerative disorders, disruption of synaptic connectivity and impaired neuronal signaling are among the early signs. When looking for potential causes of neurodegeneration, specific attention is drawn to the function of synaptic mitochondria, as the energy supply from mitochondria is crucial for normal synaptic function. Mitochondrial heterogeneity between synaptic and non-synaptic mitochondria has been described, but very little is known about possible differences between synaptic mitochondria from different brain regions. The striatum and the cerebral cortex are often affected in neurodegenerative disorders. In this study we therefore used isolated nerve terminals (synaptosomes) from female mice, striatum and cerebral cortex, to investigate differences in synaptic mitochondrial function between these two brain regions. We analyzed mitochondrial mass, citrate synthase activity, general metabolic activity and mitochondrial respiration in resting as well as veratridine-activated synaptosomes using glucose and/or pyruvate as substrate. We found higher mitochondrial oxygen consumption rate in both resting and activated cortical synaptosomes compared to striatal synaptosomes, especially when using pyruvate as a substrate. The higher oxygen consumption rate was not caused by differences in mitochondrial content, but instead corresponded with a higher proton leak in the cortical synaptic mitochondria compared to the striatal synaptic mitochondria. Our results show that the synaptic mitochondria of the striatum and cortex differently regulate respiration both in response to activation and variations in substrate conditions.
线粒体功能障碍已被证明在神经退行性疾病中发挥重要作用，如亨廷顿氏病、阿尔茨海默病和帕金森病。在这些和其他神经退行性疾病中，突触连接的破坏和神经元信号的受损是早期迹象之一。在寻找神经退行性变的潜在原因时，特别关注突触线粒体的功能，因为线粒体提供的能量对于正常的突触功能至关重要。已经描述了突触线粒体和非突触线粒体之间的线粒体异质性，但对于来自不同脑区的突触线粒体之间可能存在的差异知之甚少。纹状体和大脑皮层在神经退行性疾病中经常受到影响。因此，在这项研究中，我们使用来自雌性小鼠的分离神经末梢（突触体），即纹状体和大脑皮层，来研究这两个脑区之间突触线粒体功能的差异。我们分析了线粒体质量、柠檬酸合酶活性、一般代谢活性和线粒体呼吸，使用葡萄糖和/或丙酮酸作为底物，在静息和藜芦碱激活的突触体中。我们发现，与纹状体突触体相比，皮质突触体在静息和激活状态下的线粒体耗氧率都更高，尤其是当使用丙酮酸作为底物时。更高的耗氧率不是由线粒体含量的差异引起的，而是与皮质突触体中线粒体质子泄漏的增加有关，而纹状体突触体中的质子泄漏则较低。我们的结果表明，纹状体和大脑皮层的突触线粒体在对激活和底物条件变化的反应中，以不同的方式调节呼吸。
