PMID- 27225841 OWN - NLM STAT- MEDLINE DCOM- 20180510 LR - 20181202 IS - 1559-1174 (Electronic) IS - 1535-1084 (Print) IS - 1535-1084 (Linking) VI - 18 IP - 4 DP - 2016 Dec TI - Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics. PG - 581-592 AB - 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. FAU - Jin, Jing AU - Jin J AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. FAU - Gu, Hao AU - Gu H AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. FAU - Anders, Nicole M AU - Anders NM AD - Analytical Pharmacology Core, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Ren, Tianhua AU - Ren T AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. AD - Department of Emergency Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. FAU - Jiang, Mali AU - Jiang M AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. FAU - Tao, Michael AU - Tao M AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. FAU - Peng, Qi AU - Peng Q AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. FAU - Rudek, Michelle A AU - Rudek MA AD - Analytical Pharmacology Core, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Duan, Wenzhen AU - Duan W AD - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. wduan2@jhmi.edu. AD - Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. wduan2@jhmi.edu. AD - Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. wduan2@jhmi.edu. LA - eng GR - P30 CA006973/CA/NCI NIH HHS/United States GR - R01 NS082338/NS/NINDS NIH HHS/United States GR - S10 RR026824/RR/NCRR NIH HHS/United States GR - UL1 TR001079/TR/NCATS NIH HHS/United States PT - Journal Article DEP - 20160525 PL - United States TA - Neuromolecular Med JT - Neuromolecular medicine JID - 101135365 RN - 0 (Huntingtin Protein) RN - 0 (Neuroprotective Agents) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Animals MH - Disease Models, Animal MH - Enzyme Activation/drug effects MH - Huntingtin Protein/*toxicity MH - Huntington Disease/drug therapy/physiopathology MH - Metformin/*pharmacology MH - Mice MH - Mitochondria/drug effects MH - Mitochondrial Dynamics/*drug effects MH - Neuroprotective Agents/pharmacology PMC - PMC5112128 MID - NIHMS792803 OTO - NOTNLM OT - AMPK OT - Huntington's disease OT - Metformin OT - Mitochondria COIS- All authors have declared the sources of research funding for this manuscript and have no financial or other contractual agreements that might cause (or be perceived as causes of) conflicts of interest. EDAT- 2016/05/27 06:00 MHDA- 2018/05/11 06:00 PMCR- 2017/12/01 CRDT- 2016/05/27 06:00 PHST- 2015/11/13 00:00 [received] PHST- 2016/05/14 00:00 [accepted] PHST- 2016/05/27 06:00 [pubmed] PHST- 2018/05/11 06:00 [medline] PHST- 2016/05/27 06:00 [entrez] PHST- 2017/12/01 00:00 [pmc-release] AID - 10.1007/s12017-016-8412-z [pii] AID - 10.1007/s12017-016-8412-z [doi] PST - ppublish SO - Neuromolecular Med. 2016 Dec;18(4):581-592. doi: 10.1007/s12017-016-8412-z. Epub 2016 May 25.