Mitochondrial Respiration Changes in R6/2 Huntington's Disease Model Mice during Aging in a Brain Region Specific Manner
Mitochondrial Respiration Changes in R6/2 Huntington's Disease Model Mice during Aging in a Brain Region Specific Manner
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DOI：
10.3390/ijms21155412
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发表时间：
2020-08-01
影响因子：
5.6
通讯作者：
Squitieri, Ferdinando
中科院分区：
文献类型：
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作者：
Burtscher, Johannes;Di Pardo, Alba;Squitieri, Ferdinando
线粒体功能障碍与衰老和神经退行性疾病，如亨廷顿舞蹈病（HD）密切相关。线粒体如何在HD中受损尚不清楚，但有助于开发预防或逆转由此产生的缺陷的治疗方法。在本文中，我们研究了氧化磷酸化（OXPHOS）在幼年小鼠与成年小鼠的大脑区域之间是否存在差异，以及这种发育变化是否可能在R6/2 HD小鼠模型中受到损害。我们用高分辨率呼吸测量法研究了雌性野生型和R6/2小鼠纹状体、海马和运动皮层的OXPHOS，这些小鼠与症状前和症状性R6/2小鼠对应。我们观察到，除了皮质琥珀酸驱动的呼吸外，R6/2小鼠的oxphos控制参数也发生了类似的发育变化。虽然成年小鼠在所有分析的大脑区域中，与最大呼吸量相关的LEAK状态都有所降低，但琥珀酸驱动的呼吸仅在纹状体和皮层中减少，而nadh驱动的呼吸仅在纹状体中高于幼年小鼠。我们证明了R6/2小鼠不同脑区呼吸能力的年龄相关变化与细微偏差。揭示衰老和HD疾病进展过程中的原位氧条件和潜在底物限制是未来研究HD大脑区域脆弱性的有趣途径。
Mitochondrial dysfunction is crucially involved in aging and neurodegenerative diseases, such as Huntington's Disease (HD). How mitochondria become compromised in HD is poorly understood but instrumental for the development of treatments to prevent or reverse resulting deficits. In this paper, we investigate whether oxidative phosphorylation (OXPHOS) differs across brain regions in juvenile as compared to adult mice and whether such developmental changes might be compromised in the R6/2 mouse model of HD. We study OXPHOS in the striatum, hippocampus, and motor cortex by high resolution respirometry in female wild-type and R6/2 mice of ages corresponding to pre-symptomatic and symptomatic R6/2 mice. We observe a developmental shift in OXPHOS-control parameters that was similar in R6/2 mice, except for cortical succinate-driven respiration. While the LEAK state relative to maximal respiratory capacity was reduced in adult mice in all analyzed brain regions, succinate-driven respiration was reduced only in the striatum and cortex, and NADH-driven respiration was higher as compared to juvenile mice only in the striatum. We demonstrate age-related changes in respirational capacities of different brain regions with subtle deviations in R6/2 mice. Uncovering in situ oxygen conditions and potential substrate limitations during aging and HD disease progression are interesting avenues for future research to understand brain-regional vulnerability in HD.