Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve.
Cisplatin induces mitochondrial deficits in Drosophila larval segmental nerve.
复制标题
DOI：
10.1016/j.nbd.2016.10.003
复制
发表时间：
2017-01
影响因子：
6.1
通讯作者：
Windebank, Anthony
中科院分区：
文献类型：
--
作者：
Podratz, Jewel L.;Lee, Han;Knorr, Patrizia;Koehler, Stephanie;Forsythe, Steven;Lambrecht, Kelsey;Arias, Suzette;Schmidt, Kiley;Steinhoff, Gabrielle;Yudintsev, Georgiy;Yang, Amy;Trushina, Eugenia;Windebank, Anthony
顺铂是一种有效的化疗药物，可引起癌症患者周围神经病变。在啮齿动物背根神经节神经元中，顺铂结合核和线粒体 DNA (mtDNA)，诱导 DNA 损伤和细胞凋亡。铂-mtDNA 加合物抑制 mtDNA 复制和转录，导致线粒体降解。顺铂还会诱导成年果蝇中与神经元凋亡相关的攀爬缺陷。在这里，我们利用在运动神经元线粒体中表达绿色荧光蛋白的果蝇幼虫来观察顺铂对线粒体动力学和功能的影响。用 10 μg/ml 顺铂处理的幼虫存活正常，但存在翻正和热感应行为缺陷。泛半胱天冬酶抑制剂 p35 消除了行为。然而，免疫染色未检测到活性 caspase 3。沿轴突的线粒体膜电位下降了 27%，而线粒体中的活性氧 (ROS) 增加了 42%。线粒体轴突运输的检查显示速度、通量或线粒体长度没有变化。然而，顺铂治疗导致轴突运动过程中长时间暂停而导致更多数量的静止细胞器。这些结果表明，顺铂会诱导果蝇幼虫行为缺陷、线粒体活性降低、ROS 产生增加和线粒体暂停，但不会杀死幼虫。因此，我们确定了在顺铂诱导的周围神经病变中受影响的线粒体动力学和功能的特定方面，并且可能代表关键的治疗靶点。
Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function. Larvae treated with 10 μg/ml cisplatin had normal survival with deficiencies in righting and heat sensing behavior. Behavior was abrogated by, the pan caspase inhibitor, p35. However, active caspase 3 was not detected by immunostaining. There was a 27% decrease in mitochondrial membrane potential and a 42% increase in reactive oxygen species (ROS) in mitochondria along the axon. Examination of mitochondrial axonal trafficking showed no changes in velocity, flux or mitochondrial length. However, cisplatin treatment resulted in a greater number of stationary organelles caused by extended pausing during axonal motility. These results demonstrate that cisplatin induces behavior deficiencies in Drosophila larvae, decreased mitochondrial activity, increased ROS production and mitochondrial pausing without killing the larvae. Thus, we identified particular aspects of mitochondrial dynamics and function that are affected in cisplatin-induced peripheral neuropathy and may represent key therapeutic targets.
登录
查看更多内容
影响因子：
4.4
作者：
Johnson, Cassandra;Pankratz, Vernon S.;Velazquez, Ana I.;Aakre, Jeremiah A.;Loprinzi, Charles L.;Staff, Nathan P.;Windebank, Anthony J.;Yang, Ping
通讯作者：
Yang, Ping
影响因子：
45.3
作者：
GREGG, RW;MOLEPO, JM;STEWART, DJ
通讯作者：
STEWART, DJ
DOI：
10.1073/pnas.1106862108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Chang, Karen T.;Niescier, Robert F.;Min, Kyung-Tai
通讯作者：
Min, Kyung-Tai
影响因子：
5.4
作者：
Mehrabadi, Mohammad;Hussain, Mazhar;Asgari, Sassan
通讯作者：
Asgari, Sassan
影响因子：
7.4
作者：
Mukhopadhyay, Partha;Horvath, Bela;Zsengeller, Zsuzsanna;Zielonka, Jacek;Tanchian, Galin;Holovac, Eileen;Kechrid, Malek;Patel, Vivek;Stillman, Isaac E.;Parikh, Samir M.;Joseph, Joy;Kalyanaraman, Balaraman;Pacher, Pal
通讯作者：
Pacher, Pal