Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model.
Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model.
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DOI：
10.1016/j.nbd.2010.09.006
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发表时间：
2011-01
影响因子：
6.1
通讯作者：
Berman, Sarah B.
中科院分区：
文献类型：
--
作者：
Arnold, Beth;Cassady, Steven J.;VanLaar, Victor S.;Berman, Sarah B.
关键词：
线粒体动态特性的变化越来越多地涉及神经退行性疾病，特别是帕金森病（PD）。通常在急性毒性条件下，线粒体形态的静态变化通常用作线粒体分裂和融合变化的指标。然而，在神经元中，线粒体分裂和融合发生在轴突/树突运输、生物发生和降解的动态系统中，因此可能会随着时间的推移而相互作用和变化。我们试图探索这一点，使用慢性神经元模型（非致死性低浓度鱼藤酮超过几个星期），检查远端神经突，这可能会让洞察发生在PD的最早的变化。使用这个模型，在活的原代神经元中，我们直接量化了线粒体分裂、融合和随时间的运输，并整合了线粒体动力学的多个方面，包括形态学和生长/线粒体自噬。我们发现线粒体分裂和融合的速率随着神经元年龄的变化而变化。此外，我们发现，慢性鱼藤酮暴露最初增加的比例融合裂变，但后来，这是逆转。令人惊讶的是，尽管分裂和融合速率发生变化，但线粒体形态受到的影响最小，这表明形态可能是分裂/融合变化的不准确指标。此外，我们发现了代偿性变化的亚细胞区室化的证据，因为线粒体密度首先在远端神经突中增加，这在PD中可能是重要的，其中病理学可能从远端开始开始。我们认为鱼藤酮诱导的早期变化，如线粒体融合是补偿性的，随后伴随着有害的裂变。作为证据，在多巴胺能神经元模型中，其中慢性鱼藤酮在细胞死亡之前引起神经突损失（如PD病理学），抑制分裂防止神经突损失。这表明，异常的线粒体动力学可能有助于在PD的最早的神经病理机制。这些数据还强调，线粒体分裂和融合不会孤立地发生，并强调了分析和整合神经元中多种线粒体动态功能的重要性。
Changes in dynamic properties of mitochondria are increasingly implicated in neurodegenerative diseases, particularly Parkinson’s disease (PD). Static changes in mitochondrial morphology, often under acutely toxic conditions, are commonly utilized as indicators of changes in mitochondrial fission and fusion. However, in neurons, mitochondrial fission and fusion occur in a dynamic system of axonal/dendritic transport, biogenesis and degradation, and thus, likely interact and change over time. We sought to explore this using a chronic neuronal model (nonlethal low-concentration rotenone over several weeks), examining distal neurites, which may give insight into the earliest changes occurring in PD. Using this model, in live primary neurons, we directly quantified mitochondrial fission, fusion, and transport over time and integrated multiple aspects of mitochondrial dynamics, including morphology and growth/mitophagy. We found that rates of mitochondrial fission and fusion change as neurons age. In addition, we found that chronic rotenone exposure initially increased the ratio of fusion to fission, but later, this was reversed. Surprisingly, despite changes in rates of fission and fusion, mitochondrial morphology was minimally affected, demonstrating that morphology can be an inaccurate indicator of fission/fusion changes. In addition, we found evidence of subcellular compartmentalization of compensatory changes, as mitochondrial density increased in distal neurites first, which may be important in PD, where pathology may begin distally. We propose that rotenone-induced early changes such as in mitochondrial fusion are compensatory, accompanied later by detrimental fission. As evidence, in a dopaminergic neuronal model, in which chronic rotenone caused loss of neurites before cell death (like PD pathology), inhibiting fission protected against the neurite loss. This suggests that aberrant mitochondrial dynamics may contribute to the earliest neuropathologic mechanisms in PD. These data also emphasize that mitochondrial fission and fusion do not occur in isolation, and highlight the importance of analysis and integration of multiple mitochondrial dynamic functions in neurons.
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影响因子：
11.4
作者：
Barsoum, Mark J.;Yuan, Hua;Bossy-Wetzel, Ella
通讯作者：
Bossy-Wetzel, Ella
影响因子：
64.5
作者：
Li, Z;Okamoto, K;Sheng, M
通讯作者：
Sheng, M
影响因子：
3.6
作者：
Chernova, T;Nicotera, P;Smith, AG
通讯作者：
Smith, AG
影响因子：
4.5
作者：
Liu QA;Shio H
通讯作者：
Shio H
DOI：
10.1083/jcb.200809060
发表时间：
2009-03-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Berman SB;Chen YB;Qi B;McCaffery JM;Rucker EB 3rd;Goebbels S;Nave KA;Arnold BA;Jonas EA;Pineda FJ;Hardwick JM
通讯作者：
Hardwick JM