Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons.
Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons.
复制标题
DOI：
10.1016/j.nbd.2010.11.017
复制
发表时间：
2011-03
影响因子：
6.1
通讯作者：
Windebank, Anthony J.
中科院分区：
文献类型：
--
作者：
Podratz, Jewel L.;Knight, Andrew M.;Ta, Lauren E.;Staff, Nathan P.;Gass, Jennifer M.;Genelin, Konstantin;Schlattau, Alexander;Lathroum, Liselle;Windebank, Anthony J.
顺铂是一种基于铂的化疗剂，在30%的患者中诱导周围神经病变。周围神经病变是剂量限制性副作用，没有预防性治疗。我们以前已经表明，顺铂诱导背根神经节（DRG）感觉神经元的细胞凋亡，通过共价结合到核DNA（nDNA），导致DNA损伤，随后p53激活和线粒体介导的凋亡。我们现在证明，顺铂也直接结合到线粒体DNA（mtDNA）与nDNA相同的结合亲和力。顺铂每2166个mtDNA碱基对结合1个铂分子，每3800个nDNA碱基对结合1个铂分子。此外，顺铂处理抑制mtDNA复制，如通过5-溴-2 '-脱氧尿苷（BrdU）掺入所检测到的，并抑制线粒体基因的转录。线粒体DNA转录的相对减少与基因位于转录起始点的距离直接相关，这意味着随机形成的铂加合物阻断转录。顺铂处理的DRG神经元在体外和体内表现出线粒体空泡化和降解。总之，这些数据表明，直接mtDNA损伤可能提供了一种新的，独特的机制，顺铂诱导的神经毒性，从建立的nDNA损伤途径分开。
Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral neuropathy in 30% of patients. Peripheral neuropathy is the dose limiting side effect, which has no preventative therapy. We have previously shown that cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria. We now demonstrate that cisplatin also directly binds to mitochondrial DNA (mtDNA) with the same binding affinity as nDNA. Cisplatin binds 1 platinum molecule per 2166 mtDNA base pairs and 1 platinum molecule per 3800 nDNA base pairs. Furthermore, cisplatin treatment inhibits mtDNA replication as detected by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and inhibits transcription of mitochondrial genes. The relative reduction in mtDNA transcription is directly related to the distance the gene is located from the transcription initiation point, which implies that randomly formed platinum adducts block transcription. Cisplatin treated DRG neurons exhibit mitochondrial vacuolization and degradation in vitro and in vivo. Taken together, this data suggests that direct mtDNA damage may provide a novel, distinct mechanism for cisplatin-induced neurotoxicity separate from the established nDNA damage pathway.
登录
查看更多内容
影响因子：
2.9
作者：
RUSSELL, JW;WINDEBANK, AJ;BRIMIJOIN, WS
通讯作者：
BRIMIJOIN, WS
影响因子：
3.6
作者：
Woynarowski, JM;Chapman, WG;Juniewicz, P
通讯作者：
Juniewicz, P
DOI：
10.1146/annurev.cb.07.110191.002321
发表时间：
1991-01-01
期刊：
ANNUAL REVIEW OF CELL BIOLOGY
影响因子：
--
作者：
CLAYTON, DA
通讯作者：
CLAYTON, DA
影响因子：
2.5
作者：
Fischer, SJ;Podratz, JL;Windebank, AJ
通讯作者：
Windebank, AJ
影响因子：
6.1
作者：
McDonald, ES;Windebank, AJ
通讯作者：
Windebank, AJ