Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans.
Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans.
复制标题
DOI：
10.1091/mbc.e09-08-0673
复制
发表时间：
2010-03-15
影响因子：
3.3
通讯作者：
Roth MG
中科院分区：
文献类型：
--
作者：
Zubovych IO;Straud S;Roth MG
线粒体基因突变和OX-Phos抑制剂使秀丽隐杆线虫对多种药物产生耐药性。抗氧化剂NAC阻止这种耐药性，表明需要一种对ROS反应的机制。呼吸抑制剂产生的抗性在缺乏线虫PKCε同源物的线粒体突变体中降低。在之前的遗传筛选中，秀丽隐杆线虫突变体在抗有丝分裂药物hemiasterlin的存在下存活，我们发现了8个强突变体。其中两种被发现对多种毒素具有抗性，在其中一种中，我们发现了phb-2的错义突变，它编码线粒体蛋白禁止蛋白2。在这里，我们确定了另外两个赋予耐药性的突变，spg-7和har-1，也在编码线粒体蛋白的基因中。其他线粒体突变体isp-1、eat-3和clk-1也被发现具有耐药性。呼吸复合物抑制剂，FCCP和寡霉素，以及活性氧（ROS）的生产者，百草枯，都能将野生型蠕虫从半米斯特林毒性中拯救出来。缺乏线粒体超氧化物歧化酶（MnSOD）的蠕虫具有中度耐药，在phb-2、har-1和spg-7突变体中消除MnSOD可增强耐药性。抗氧化剂n -乙酰-l-半胱氨酸阻止线粒体抑制剂拯救野生型蠕虫免受hemiasterlin的侵害，并使突变体对毒素敏感，这表明对ROS敏感的机制是触发秀丽隐杆线虫耐药的必要条件。利用遗传学，我们发现这种耐药性需要pkc-1，即秀丽隐杆线虫与人类pkc- ε的同源物。
Mutations in mitochondrial genes and inhibitors of OX-Phos make Caenorhabditis elegans resistant to multiple drugs. The anti-oxidant NAC prevents this drug-resistance, indicating that a mechanism responsive to ROS is required. The resistance generated by inhibitors of respiration is reduced in mitochondrial mutants that lack the C. elegans ortholog of PKCε. In a previous genetic screen for Caenorhabditis elegans mutants that survive in the presence of an antimitotic drug, hemiasterlin, we identified eight strong mutants. Two of these were found to be resistant to multiple toxins, and in one of these we identified a missense mutation in phb-2, which encodes the mitochondrial protein prohibitin 2. Here we identify two additional mutations that confer drug resistance, spg-7 and har-1, also in genes encoding mitochondrial proteins. Other mitochondrial mutants, isp-1, eat-3, and clk-1, were also found to be drug-resistant. Respiratory complex inhibitors, FCCP and oligomycin, and a producer of reactive oxygen species (ROS), paraquat, all rescued wild-type worms from hemiasterlin toxicity. Worms lacking mitochondrial superoxide dismutase (MnSOD) were modestly drug-resistant, and elimination of MnSOD in the phb-2, har-1, and spg-7 mutants enhanced resistance. The antioxidant N-acetyl-l-cysteine prevented mitochondrial inhibitors from rescuing wild-type worms from hemiasterlin and sensitized mutants to the toxin, suggesting that a mechanism sensitive to ROS is necessary to trigger drug resistance in C. elegans. Using genetics, we show that this drug resistance requires pkc-1, the C. elegans ortholog of human PKCε.
登录
查看更多内容
DOI：
10.1073/pnas.76.3.1333
发表时间：
1979-01-01
影响因子：
11.1
作者：
EMMONS, SW;KLASS, MR;HIRSH, D
通讯作者：
HIRSH, D
影响因子：
4.5
作者：
Baughman JM;Nilsson R;Gohil VM;Arlow DH;Gauhar Z;Mootha VK
通讯作者：
Mootha VK
影响因子：
4.5
作者：
Kanazawa, Takayuki;Zappaterra, Mauro D.;Hasegawa, Ayako;Wright, Ashley P.;Newman-Smith, Erin D.;Buttle, Karolyn F.;McDonald, Kent;Mannella, Carmen A.;van der Bliek, Alexander M.
通讯作者：
van der Bliek, Alexander M.
影响因子：
4.8
作者：
Kayser, EB;Sedensky, MM;Hoppel, CL
通讯作者：
Hoppel, CL
影响因子：
10.8
作者：
Brennan, Jonathan P.;Southworth, Richard;Shattock, Michael J.
通讯作者：
Shattock, Michael J.