Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics.
Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics.
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DOI：
10.1007/s12017-016-8412-z
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发表时间：
2016-12
影响因子：
3.5
通讯作者：
Duan, Wenzhen
中科院分区：
文献类型：
--
作者：
Jin, Jing;Gu, Hao;Anders, Nicole M.;Ren, Tianhua;Jiang, Mali;Tao, Michael;Peng, Qi;Rudek, Michelle A.;Duan, Wenzhen
亨廷顿病（Huntington's disease，HD）是由亨廷顿基因CAG重复序列病理性延长引起的一种破坏性神经退行性疾病。热量限制（CR）已成为最可重复的环境干预，以改善健康和延长寿命。我们已经证明，在HD小鼠模型中，CR延迟发作并减缓疾病进展。二甲双胍是一种抗糖尿病药物，通过在多个水平上作用于细胞代谢来模拟CR。长期服用二甲双胍可改善小鼠的健康状况和寿命。在本研究中，我们发现二甲双胍可使细胞免于突变型亨廷顿蛋白（HTT）诱导的毒性，如细胞释放的乳酸脱氢酶（LDH）减少和表达突变型HTT的细胞中ATP水平保持不变所示。进一步的机制研究表明，二甲双胍激活AMP活化蛋白激酶（AMPK），抑制AMPK活化降低其对突变HTT毒性的保护作用，表明AMPK介导二甲双胍对HD细胞的保护作用。此外，二甲双胍处理防止了线粒体膜去极化和过度分裂，并调节了HD细胞中受干扰的线粒体动力学。我们证实二甲双胍口服给药后可穿过血脑屏障，并激活小鼠脑中的AMPK。我们的研究结果要求进一步评价二甲双胍在HD治疗中的临床潜力。
Huntington’s disease (HD) is a devastating neurodegenerative disease caused by the pathological elongation of the CAG repeats in the huntingtin gene. Caloric restriction (CR) has been the most reproducible environmental intervention to improve health and prolong life span. We have demonstrated that CR delayed onset and slowed disease progression in a mouse model of HD. Metformin, an antidiabetic drug, mimics CR by acting on cell metabolism at multiple levels. Long-term administration of metformin improved health and life span in mice. In this study, we showed that metformin rescued cells from mutant huntingtin (HTT)-induced toxicity, as indicated by reduced lactate dehydrogenase (LDH) release from cells and preserved ATP levels in cells expressing mutant HTT. Further mechanistic study indicated that metformin activated AMP-activated protein kinase (AMPK) and that inhibition of AMPK activation reduced its protective effects on mutant HTT toxicity, suggesting that AMPK mediates the protection of metformin in HD cells. Furthermore, metformin treatment prevented mitochondrial membrane depolarization and excess fission, and modulated the disturbed mitochondrial dynamics in HD cells. We confirmed that metformin crossed the blood-brain barrier after oral administration and activated AMPK in the mouse brain. Our results urge further evaluation of the clinical potential for use of metformin in HD treatment.
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DOI：
10.1083/jcb.201105010
发表时间：
2011-07-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ju TC;Chen HM;Lin JT;Chang CP;Chang WC;Kang JJ;Sun CP;Tao MH;Tu PH;Chang C;Dickson DW;Chern Y
通讯作者：
Chern Y
影响因子：
7.4
作者：
Reddy, P. Hemachandra
通讯作者：
Reddy, P. Hemachandra
影响因子：
3.7
作者：
Jin YN;Yu YV;Gundemir S;Jo C;Cui M;Tieu K;Johnson GV
通讯作者：
Johnson GV
影响因子：
23.9
作者：
Wang, Jing;Gallagher, Denis;Miller, Freda D.
通讯作者：
Miller, Freda D.
影响因子：
16.6
作者：
Martin-Montalvo, Alejandro;Mercken, Evi M.;Mitchell, Sarah J.;Palacios, Hector H.;Mote, Patricia L.;Scheibye-Knudsen, Morten;Gomes, Ana P.;Ward, Theresa M.;Minor, Robin K.;Blouin, Marie-Jose;Schwab, Matthias;Pollak, Michael;Zhang, Yongqing;Yu, Yinbing;Becker, Kevin G.;Bohr, Vilhelm A.;Ingram, Donald K.;Sinclair, David A.;Wolf, Norman S.;Spindler, Stephen R.;Bernier, Michel;de Cabo, Rafael
通讯作者：
de Cabo, Rafael